Tel Aviv University Researchers Target Drug-Resistant Ovarian Tumors with Nanotechnology

Tel Aviv University researchers devise a fast and effective nanotechnology — called “gagomers” — to combat drug-resistant ovarian cancer.

Professor Dan Peer of Tel Aviv University’s Department of Cell Research and Immunology has proposed a new strategy to tackle drug-resistant ovarian cancer using a new nanoscale drug-delivery system designed to target specific cancer cells. The study was published in February in the journal ACS Nano.

Nanotechnology usually refers to an object that is 1-to–100 nanometers in size. A nanometer is a billionth of a meter. By comparison, the width of a strand of hair is approximately 100,000 times larger than a nanometer.

Prof. Peer and his team — Keren Cohen and Rafi Emmanuel from Peer’s Laboratory of Nanomedicine and Einat Kisin-Finfer and Doron Shabbat, from TAU’s Department of Chemistry — devised a cluster of nanoparticles called “gagomers,” which are made from fats and coated with a kind of polysugar. When filled with chemotherapy drugs (in this case doxorubicin), these clusters accumulate in tumors, producing dramatic therapeutic benefits.

The objective of Peer’s research is two-fold: to provide a specific target for anti-cancer drugs to increase their therapeutic benefits, and to reduce the toxic side effects of anti-cancer therapies.

Why Chemotherapy Fails

According to Prof. Peer, traditional courses of chemotherapy are not an effective line of attack. Chemotherapy’s failing lies in the inability of the medicine to be absorbed and maintained within the tumor cell long enough to destroy it. In most cases, the chemotherapy drug is almost immediately ejected by the cancer cell, severely damaging the healthy organs that surround it, leaving the tumor cell intact.

Gagomers (labeled in color) accumulating on ovarian cancer cells. (Credit: Image courtesy of American Friends of Tel Aviv University)

Gagomers (labeled in color) accumulating on ovarian cancer cells.
(Credit: Image courtesy of American Friends of Tel Aviv University)

But with this new nanotechnology therapy, Peer and his colleagues saw a 25-fold increase in tumor-accumulated medication and a dramatic dip in toxic accumulation in healthy organs. Tested on laboratory mice, the gagomer affects a change in drug-resistant ovarian cancer tumor cells. Receptors on tumor cells recognize the sugar that encases the gagomer, allowing the binding gagomer to slowly release tiny particles of chemotherapy into the cancerous cell. As more and more of the drug accumulates within the tumor cell, the cancer cells begin to die off within 24-48 hours. In this preclinical setting, the doxorubicin encased gagomers even outperformed pegylated liposomal doxorubicin (Doxil) — a standard of care drug used to treat recurrent ovarian cancer.

“Tumors become resistant very quickly. Following the first, second, and third courses of chemotherapy, the tumors start pumping drugs out of the cells as a survival mechanism,” said Prof. Peer. “Most patients with tumor cells beyond the ovaries relapse and ultimately die due to the development of drug resistance. We wanted to create a safe drug-delivery system, which wouldn’t harm the body’s immune system or organs.”

A Personal Perspective

Prof. Peer chose to tackle ovarian cancer in his research because his mother-in-law passed away at the age of 54 from the disease. “She received all the courses of chemotherapy and survived only a year and a half,” Peer said. “She died from the drug-resistant aggressive tumors.”

“At the end of the day, you want to do something natural, simple, and smart. We are committed to try to combine both laboratory and therapeutic arms to create a less toxic, focused drug that combats aggressive drug-resistant cancerous cells,” said Prof. Peer. “We hope the concept will be harnessed in the next few years in clinical trials on aggressive tumors,” said Prof. Peer.

Sources:

FDA Approves Clinical Protocol for Additional Phase 1 Study of TKM-PLK1 in Primary Liver Cancer or Liver Metastases

The U.S. Food and Drug Administration approves the clinical protocol for an additional Phase 1 study of TKM-PLK1 in patients with either primary liver cancer or liver metastases associated with select cancers including ovarian.

RNA Interference

Nucleic acids are molecules that carry genetic information and include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). Together these molecules form the building blocks of life. DNA contains the genetic code or “blueprint” used in the development and functioning of all living organisms, while one type of RNA (i.e., “messenger RNA” or mRNA) helps to translate that genetic code into proteins by acting as a messenger between the DNA instructions located in the cell nucleus and the protein synthesis which takes place in the cell cytoplasm (i.e., outside the cell nucleus, but inside the outer cell membrane). Accordingly, DNA is first copied or transcribed into mRNA, which, in turn, gets translated or synthesized into protein.

The molecular origin of many diseases results from either the absence or over-production of specific proteins. “RNA interference” (RNAi) is a mechanism through which gene expression is inhibited at the translation stage, thereby disrupting the protein production. RNAi is considered one of the most important discoveries in the field of molecular biology. Andrew Fire, Ph.D., and Craig C. Mello, Ph.D. shared the 2006 Nobel Prize in Physiology or Medicine for work that led to the discovery of the RNAi mechanism.  Because many diseases – cancer, metabolic, infectious and others – are caused by the inappropriate activity of specific genes, the ability to silence genes selectively through RNAi offers the potential to revolutionize the way we treat disease and illness by creating a new class of drugs aimed at eliminating specific gene-products or proteins from the cell. RNAi has been convincingly demonstrated in preclinical models of oncology, influenza, hepatitis, high cholesterol, diabetes, macular degeneration, Parkinson’s disease, and Huntington’s disease.

Small Interfering RNA 

While the mechanism itself is termed “RNAi,” the therapeutic agents that exert the effect are known as “small interfering RNAs” or siRNAs. Sequencing of the human genome has provided the information needed to design siRNA therapeutics directed against a wide range of disease-causing proteins. Based on the mRNA sequence for the target protein, a siRNA therapeutic can be designed relatively quickly compared to the time needed to synthesize and screen conventional small molecule drugs. Moreover, siRNA-based therapeutics are able to bind to a target protein mRNA with great specificity. When siRNA are introduced into the cell cytoplasm they are rapidly incorporated into an “RNA-induced silencing complex” (RISC) and guided to the target protein mRNA, which is then cut and destroyed, preventing the subsequent production of the target protein. The RISC can remain stable inside the cell for weeks, destroying many more copies of the target mRNA and maintaining target protein suppression for long periods of time.

To our knowledge, there are no siRNAs approved yet for medical use outside of a clinical trial, however, a number of R&D initiatives and clinical trials are currently underway, with one of the main areas of research focused on delivery. Because siRNAs are large, unstable molecules, they are unable to access target cells. Delivery technology is required to stabilize these drugs in the human blood stream, allow efficient delivery to the target cells, and facilitate uptake and release into the cell cytoplasm. Tekmira Pharmaceuticals Corporation, a leading developer of RNAi therapeutics has focused its research on identifying lipid nanoparticles (LNPs) that can overcome the challenges of delivering siRNAs.

TKM-PLK1 

TKM-PLK1 is being developed as a novel anti-tumor drug in the treatment of cancer. LNPs are particularly well suited for the delivery of siRNA to treat cancer because the lipid nanoparticles preferentially accumulate within tissues and organs having leaky blood vessels, such as cancerous tumors. Once at the target site, LNPs are taken up by tumor cells and the siRNA payload is delivered inside the cell where it reduces expression of the target protein. Through careful selection of the appropriate molecular targets, LNPs are designed to have potent anti-tumor activity yet be well tolerated by healthy tissue adjacent to the tumor.

Tekmira has taken advantage of this passive targeting effect to develop an siRNA directed against PLK1 (polo-like kinase 1), a protein involved in tumor cell proliferation. Inhibition of PLK1 prevents the tumor cell from completing cell division, resulting in cell cycle arrest and cell death.

Because the standard of care for cancer treatment often involves the use of drug combination therapies, Tekmira has selected gene targets for its oncology applications that synergize with conventional drugs that are currently in use. TKM-PLK1 has the potential to provide both direct tumor cell killing and sensitization of tumor cells to the effects of chemotherapy drugs.

Phase 1 Study of TKM-PLK1 in Primary Liver Cancer or Liver Metastases

Tekmira, along with its collaborators at the U.S. National Cancer Institute (NCI), announced that they have received approval from the U.S. Food and Drug Administration (FDA) to proceed with a new Phase 1 clinical trial for Tekmira’s lead oncology product, TKM-PLK1. This trial, run in parallel with the ongoing Phase 1 trial of TKM-PLK1 (for adult patients with solid tumors or lymphomas that are refractory to standard therapy), provides Tekmira with an early opportunity to validate the mechanism of drug action.

“Patients in this new study, who will have either primary liver cancer or liver metastases, will receive TKM-PLK1 delivered directly into the liver via Hepatic Artery Infusion (HAI). The trial design will allow us to measure tumor delivery, polo-like kinase 1 (PLK1) messenger RNA knockdown, and RNA interference (RNAi) activity in tumor biopsies from all of the patients treated,” said Dr. Mark J. Murray, Tekmira’s President and CEO.

“This NCI clinical trial will run in parallel with our multi-center TKM-PLK1 solid tumor Phase 1 trial, currently underway at three centers in the United States. Working together on this clinical trial with our collaborators at the NCI will allow us to develop an even more robust data package to inform subsequent TKM-PLK1 development. We expect to have interim TKM-PLK1 clinical data before the end of 2011,” added Dr. Murray.

The NCI trial is a Phase 1 multiple-dose, dose escalation study testing TKM-PLK1 in patients with unresectable colorectal, pancreatic, gastric, breast, ovarian and esophageal cancers with liver metastases, or primary liver cancers. These patients represent a significant unmet medical need as they are not well served by currently approved treatments.

The primary objectives of the trial include evaluation of the feasibility of administering TKM-PLK1 via HAI, and characterization of the pharmacokinetics and pharmacodynamics of TKM-PLK1. Pharmacodynamic measurements will examine the effect of the drug on the patient’s tumors, specifically aiming to confirm PLK1 knockdown and RNAi activity. Typically reserved for later stage trials, pharmacodynamic measurements are facilitated in this Phase 1 trial in part through the unique capabilities of the NCI Surgery Branch. Secondary objectives of the trial include establishing maximum tolerated dose and to evaluate response rate.

About the National Cancer Institute

The National Cancer Institute (NCI) is one of 27 institutes and centers under the oversight of the U.S. National Institutes of Health (NIH), and is the primary cancer medical research agency in the U.S. The TKM-PLK1 trial will involve investigators at the NCI’s Center for Cancer Research (CCR) on the main NIH campus located in Bethesda, Maryland. The CCR is home to more than 250 scientists and clinicians working in intramural research at the NCI. CCR’s investigators include some of the worlds most experienced basic, clinical, and translational scientists who work together to advance our knowledge of cancer and develop new therapies.

About TKM-PLK1

TKM-PLK1 targets polo-like kinase 1, or PLK1, a cell cycle protein involved in tumor cell proliferation and a validated oncology target. Cancer patients whose tumors express high levels of PLK1 have a relatively poor prognosis. Inhibition of PLK1 prevents tumor cells from completing cell division, resulting in cell cycle arrest and cancer cell death.

About RNAi and Tekmira’s LNP Technology

RNAi therapeutics have the potential to treat a broad number of human diseases by “silencing” disease causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi therapeutics, such as “siRNAs,” require delivery technology to be effective systemically. LNP technology is one of the most widely used siRNA delivery approaches for systemic administration. Tekmira’s LNP technology (formerly referred to as “stable nucleic acid-lipid particles” or SNALP) encapsulates siRNAs with high efficiency in uniform lipid nanoparticles which are effective in delivering RNAi therapeutics to disease sites in numerous preclinical models. Tekmira’s LNP formulations are manufactured by a proprietary method which is robust, scalable and highly reproducible and LNP-based products have been reviewed by multiple FDA divisions for use in clinical trials. LNP formulations comprise several lipid components that can be adjusted to suit the specific application.

About Tekmira Pharmaceuticals Corporation

Tekmira Pharmaceuticals Corporation is a biopharmaceutical company focused on advancing novel RNAi therapeutics and providing its leading lipid nanoparticle delivery technology to pharmaceutical partners. Tekmira has been working in the field of nucleic acid delivery for over a decade and has broad intellectual property covering LNPs. Further information about Tekmira can be found at www.tekmirapharm.com. Tekmira is based in Vancouver, British Columbia, Canada.

Source

Clinical Trial Information

  • A Phase 1 Dose Escalation Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of Intravenous TKM-080301 [a/k/a TKM-PLK1 or PLK1 SNALP] in Patients With Advanced Solid Tumors [or Lymphomas], ClinicalTrials.gov Identifier: NCT01262235. [Note: This clinical trial summary relates to the ongoing Phase 1 TKM-PLK1  solid tumor clinical trial. We will post the second Phase 1 TKM-PLK1 clinical trial summary with respect to primary liver cancer and liver metastases once it becomes publicly available]
Additional Information
  • Wang J, et al. Delivery of siRNA therapeutics: barriers and carriers. AAPS J. 2010 Dec;12(4):492-503. Epub 2010 Jun 11. Review. PubMed PMID: 20544328; PubMed Central PMCID: PMC2977003.

Novel Cancer-Targeting “Cornell Dot” Nanoparticle Approved for First-In-Human Clinical Trial

“Cornell Dots” — brightly glowing nanoparticles — may soon be used to light up cancer cells to aid in diagnosing and treating cancer. The U.S. Food and Drug Administration (FDA) has approved the first clinical trial in humans of the new technology. It is the first time the FDA has approved using an inorganic material in the same fashion as a drug in humans.

“Cornell Dots” (or “C dots”) — brightly glowing nanoparticles — may soon be used to light up cancer cells to aid in diagnosing and treating cancer. The U.S. Food and Drug Administration (FDA) has approved the first clinical trial in humans of the new technology. It is the first time the FDA has approved using an inorganic material in the same fashion as a drug in humans.

Michelle Bradbury, M.D., Ph.D., Clinician-Scientist, Neuroradiology Service, Memorial Sloan-Kettering Cancer Center; Assistant Professor, Radiology, Weill Cornell Medical College; Lead Study Investigator

Researchers at Memorial Sloan-Kettering Cancer Center’s Nanotechnology Center, along with collaborators at Cornell University and Hybrid Silica Technologies, have received approval for their first Investigational New Drug Application (IND) from the FDA for an ultrasmall silica inorganic nanoparticle platform for targeted molecular imaging of cancer, which may be useful for cancer treatment in the future. Center researchers are about to launch their first-in-human clinical trial in melanoma patients using this first-of-its-kind inorganic nanoparticle to be approved as a drug. “This is a very exciting and important first step for this new particle technology that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers,” said Michelle Bradbury, M.D., Ph.D., a clinician-scientist on Memorial Sloan-Kettering’s Neuroradiology Service and an assistant professor of radiology at Weill Cornell Medical College, who is the lead investigator of the study, along with Snehal Patel, M.D., a surgeon on Memorial Sloan-Kettering’s Head and Neck Service, who is a co-principal investigator.

“This is a very exciting and important first step for this new particle technology that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers.”

— Michelle Bradbury, M.D., Ph.D., lead investigator of the study and clinician-scientist on Memorial Sloan-Kettering’s Neuroradiology Service and an assistant professor of radiology at Weill Cornell Medical College

C dots were initially developed as optical probes at Cornell University, Ithaca, by Ulrich Wiesner, Ph.D., a professor of materials science and engineering who, along with Hybrid Silica Technologies, the supplier of C dots, has spent the past eight years precisely engineering these particles. C dots are silica spheres less than 8 nanometers in diameter that enclose several dye molecules. (A nanometer is one-billionth of a meter, about the length of three atoms in a row.) The silica shell, essentially glass, is chemically inert and small enough to pass through the body and out in the urine. For clinical applications, the dots are coated with polyethylene glycol so the body will not recognize them as foreign substances.

C dots were subsequently modified at Memorial Sloan-Kettering for use in PET (positron emission tomography) imaging. C dots are tiny silica spheres that contain dye that glows three times more brightly than simple free dyes when excited by light of a specific wavelength. C dots can “light up” cancer cells, and act as tumor tracers for tracking the movement of cells and assisting in the optical diagnosis of tumors near the skin surface. The attachment of a radioactive label produces a new generation of multimodal (PET-optical) particle probes that additionally enable deeper detection, imaging, and monitoring of drug delivery using three-dimensional PET techniques.

Ulrich Wiesner, Ph.D. (left), a Cornell University Professor of Materials Science & Engineering, works with graduate students Jennifer Drewes & Kai Ma to characterize the size & brightness of C dots in their Bard Hall lab. (Photo: Jason Koski/University Photography)

C dots can be tailored to any particle size. Previous imaging experiments in mice conducted by the Memorial Sloan-Kettering team showed that particles of a very small size (in the 5 to 7 nanometer range) could be retained in the bloodstream and efficiently cleared through the kidneys after applying a neutral surface coat. More recently, the research team molecularly customized C dots to create a new particle platform, or probe, that can target surface receptors or other molecules expressed on tumor surfaces and that can be cleared through the kidneys.

Using PET scans, C dots can be imaged to evaluate various biological properties of the tumors, including tumor accumulation, spread of metastatic disease to lymph nodes and distant organs, and treatment response to therapy. The information gained from imaging tumors targeted with this multimodal platform may also assist physicians in defining tumor borders for surgery, and improving real-time visualization of small vascular beds, anatomic channels, and neural structures during surgery.

The purpose of this trial is to evaluate the distribution, tissue, uptake, and safety of the particles in humans by PET imaging. This study will provide data that will serve as a baseline to guide the design of future surgical and oncologic applications in the clinic. “The use of PET imaging is an ideal imaging technology for sensitively monitoring very small doses of this new particle probe in first-in-human trials,” added Steven Larson, M.D., Chief of Memorial Sloan-Kettering’s Nuclear Medicine Service.

Memorial Sloan-Kettering nanochemist Oula Penate Medina, Ph.D., notes that “this is an important trial in that it will help to answer a number of key questions regarding future potential applications of this multimodal system. Once the door has been opened, new and emerging fields, such as targeted drug delivery, can be investigated. We expect that these particles can be adapted for multiple clinical uses, including the early diagnosis and treatment of various cancers, as well as for sensing changes in the microenvironment.”

“This clinical trial is the culmination of a longstanding collaborative effort with our colleagues at Cornell and Hybrid Silica Technologies, as well as a testament to our own institutional colleagues here at the Center,” Dr. Bradbury said. “With the support of many, in particular the Office of Clinical Research, we’ve pushed to translate the C dots from a laboratory idea to our first FDA IND-approved inorganic nanomedicine drug product to be tested in the clinic,” Dr. Bradbury said.

The work was funded in part by the Clinical and Translational Science Center, Weill Cornell Medical College, the Cornell Nanobiology Center, and the National Institutes of Health (NIH) Small-Animal Imaging Research Program (SAIRP). In addition to Drs. Bradbury, Penante-Medina, Larson, Patel, and Wiesner, the following Memorial Sloan-Kettering investigators contributed to and/or supported this work: Pat Zanzonico, Ph.D.; Heiko Schöder, M.D.; Elisa De Stanchina, Ph.D.; Hedvig Hricak, M.D., Ph.D., Chair of the Department of Radiology; as well as Hooisweng Ow, Ph.D., of Hybrid Silica Technologies, Inc.; Memorial Sloan-Kettering’s Office of Clinical Research; and the Cyclotron Core.

Sources:

Outside-the-Body Filtration Device May Reduce Ovarian Cancer Cells In Abdominal Fluid

A paper published in the January issue of the journal Nanomedicine could provide the foundation for a new ovarian cancer treatment option — one that would use an outside-the-body filtration device to remove a large portion of the free-floating cancer cells that often create secondary tumors.

Schematic shows how fluids containing ovarian cancer cells could be removed from the body, treated with magnetic nanoparticles to remove the cells, then returned to the body. (Courtesy of Ken Scarberry)

Magnetic nanoparticles suspended in a liquid are attracted to a magnet. The nanoparticles could be attached to cancer cells and then removed from the body with magnetic filtration. (Credit: Gary Meek)

A paper published in the January issue of the journal Nanomedicine could provide the foundation for a new ovarian cancer treatment option — one that would use an outside-the-body filtration device to remove a large portion of the free-floating cancer cells that often create secondary tumors.

Researchers at the Georgia Institute of Technology have formed a startup company and are working with a medical device firm to design a prototype treatment system that would use magnetic nanoparticles engineered to capture cancer cells. Added to fluids removed from a patient’s abdomen, the magnetic nanoparticles would latch onto the free-floating cancer cells, allowing both the nanoparticles and cancer cells to be removed by magnetic filters before the fluids are returned to the patient’s body.

In mice with free-floating ovarian cancer cells, a single treatment with an early prototype of the nanoparticle-magnetic filtration system captured enough of the cancer cells that the treated mice lived nearly a third longer than untreated ones. The researchers expect multiple treatments to extend the longevity benefit, though additional research will be needed to document that — and determine the best treatment options.

“Almost no one dies from primary ovarian cancer,” said Dr. John McDonald, a professor in Georgia Tech’s School of Biology and chief research scientist of Atlanta’s Ovarian Cancer Institute. “You can remove the primary cancer, but the problem is metastasis. A good deal of the metastasis in ovarian cancer comes from cancer cells sloughing off into the abdominal cavity and spreading the disease that way.”

The removal system being developed by McDonald and postdoctoral fellow Ken Scarberry — who is also CEO of startup company Sub-Micro — should slow tumor progression in humans. It may reduce the number of free-floating cancer cells enough that other treatments, and the body’s own immune system, could keep the disease under control.

Professor John McDonald (standing) and postdoctoral fellow Ken Scarberry examine statistical data from their study of a potential new treatment option for ovarian cancer. (Credit: Gary Meek)

“If you can reduce metastasis, you can improve the lifespan of the person with the disease and get a better chance of treating it effectively,” said McDonald. “One goal is to make cancer a chronic disease that can be effectively treated over an extended period of time. If we can’t cure it, perhaps we can help people to live with it.”

Earlier in vitro studies published by the authors of the Nanomedicine paper showed that the magnetic nanoparticles could selectively remove human ovarian cancer cells from ascites fluid, which builds up in the peritoneal cavities of ovarian cancer patients. The nanoparticles are engineered with ligands that allow them to selectively attach to cancer cells.

The researchers believe that treating fluid removed from the body avoids potential toxicity problems that could result from introducing the nanoparticles into the body, though further studies are needed to confirm that the treatment would have no adverse effects.

The recently reported study in Nanomedicine used three sets of female mice to study the benefit of the nanoparticle-magnetic filtration system. Each mouse was injected with approximately 500,000 murine ovarian cancer cells, which multiply rapidly — each cell doubling within approximately 15 hours.

In the experimental group, the researchers — who included research scientist Roman Mezencev — removed fluid from the abdomens of the mice immediately after injection of the cancer cells. They then added the magnetic nanoparticles to the fluid, allowed them to mix, then magnetically removed the nanoparticles along with the attached cancer cells before returning the fluid. The steps were repeated six times for each mouse.

One control group received no treatment at all, while a second control group underwent the same treatment as the experimental group — but without the magnetic nanoparticles. Mice in the two control groups survived a median of 37 days, while the treated mice lived 12 days longer — a 32 percent increase in longevity.

Though much more research must be done before the technique can be tested in humans, McDonald and Scarberry envision a system very similar to what kidney dialysis patients now use, but with a buffer solution circulated through the peritoneal cavity to pick up the cancer cells.

“What we are developing is akin to hemofiltration or peritoneal dialysis in which the patient could come into a clinic and be hooked up to the device a couple of times a week,” said Scarberry. “The treatment is not heavily invasive, so it could be repeated often.”

The new treatment could be used in conjunction with existing chemotherapy and radiation. Reducing the number of free-floating cancer cells could allow a reduction in chemotherapy, which often has debilitating side effects, Scarberry said. The new treatment system could be used to capture spilled cancer cells immediately after surgery on a primary tumor.

The researchers hope to have a prototype circulation and filtration device ready for testing within three years. After that will come studies into the best treatment regimen, examining such issues as the number of magnetic nanoparticles to use, the number of treatments and treatment spacing. If those are successful, the company will work with the FDA to design human clinical trials.

The researchers also studying how their magnetic nanoparticles could be engineered to capture ovarian cancer stem cells, which are not affected by existing chemotherapy. Removing those cells could help eliminate a potent source of new cancer cells.

The research has been supported by the Georgia Research Alliance (GRA), the Ovarian Cancer Institute, the Robinson Family Foundation and the Deborah Nash Harris Endowment. A member of Georgia Tech’s Advanced Technology Development Center (ATDC) startup accelerator program and a GRA VentureLab company, Sub-Micro has also raised private funding to support its prototype development.

Challenges ahead include ensuring that nanoparticles cannot bypass the filtration system to enter the body, and controlling the risk of infection caused by opening the peritoneal cavity.

Beyond cancer, the researchers believe their approach could be useful for treating other diseases in which a reduction in circulating cancer cells or virus particles could be useful. Using magnetic nanoparticles engineered to capture HIV could help reduce viral content in the bloodstream, for instance.

“A technology like this has many different possibilities,” said Scarberry. “We are currently developing the technology to control the metastatic spread of ovarian cancer, but once we have a device that can efficiently and effectively isolate cancer cells from circulating fluids, including blood, we would have other opportunities.”

Sources:

Additional Information:

Lab-On-A-Chip: Veridex & MGH Collaborate On Next-Generation Circulating Tumor Cell Test

Veridex, LLC announces a collaboration with Massachusetts General Hospital to develop and commercialize a next-generation circulating tumor cell technology for capturing, counting and characterizing tumor cells found in patients’ blood.

Yesterday, Veridex, LLC (Veridex) announced a collaboration with Massachusetts General Hospital (MGH) to develop and commercialize a next-generation circulating tumor cell (CTC) technology for capturing, counting and characterizing tumor cells found in patients’ blood. The collaboration will involve Ortho Biotech Oncology Research & Development (ORD), a unit of Johnson & Johnson Pharmaceutical Research & Development. It focuses on the development of a next-generation system that will enable CTCs to be used both by oncologists as a diagnostic tool for personalizing patient care, as well as by researchers to accelerate and improve the process of drug discovery and development.

The collaboration will rely on the collective scientific, technical, clinical, and commercial expertise between the partners: MGH’s experience in clinical research and novel CTC technologies; the experience of Veridex as the only diagnostics company to have brought CTC technology to the U.S. market as an FDA-cleared in vitro diagnostic (IVD) assay ( “CellSearch® CTC Test”) for capturing and counting the number of tumor cells in the blood to help inform patients and their physicians about prognosis and overall survival in certain types of metastatic cancers; and ORD’s expertise in oncology therapeutics, biomarkers and companion diagnostics.  The platform to be developed will be a bench-top system to specifically isolate and explore the biology of rare cells at the protein, RNA and DNA levels.

“This new technology has the potential to facilitate an easy-to-administer, non-invasive blood test that would allow us to count tumor cells, and to characterize the biology of the cells,” said Robert McCormack, Head of Technology Innovation and Strategy, Veridex. “Harnessing the information contained in these cells in an in vitro clinical setting could enable tools to help select treatment and monitor how patients are responding.”

“The role of CTCs in drug discovery and development is growing as new technologies allow us to use CTCs for the first time as templates for novel DNA, RNA and protein biomarkers,” said Nicholas Dracopoli, Vice President, Biomarkers, ORD. “Given the demand for actionable data to guide personalized medicine for patients with cancer, there is a rapidly growing need for advanced, automated non-invasive technologies that can aid in selection of treatment and monitor response throughout the course of their disease.”

Mehmet Toner, Ph.D., Professor of Surgery, Massachusetts General Hospital (MGH) & Harvard Medical School; Director, MGH BioMicro- ElectroMechanical Systems Resource Center

“The challenging goal of sorting extremely rare circulating tumor cells from blood requires continuous technological, biological and clinical innovation to fully explore the utility of these precious cells in clinical oncology,” said Mehmet Toner, Ph.D., director of the BioMicroElectroMechanical Systems Resource Center in the MGH Center for Engineering in Medicine. “We have developed and continue to develop a broad range of technologies that are evolving what we know about cancer and cancer care. This collaboration is an opportunity to apply our past learning to the advancement of a platform that will ultimately benefit patients with cancer.”

Building on its successful development and evolution of CTC technology, as well as contributions to the body of science in the CTC field, MGH aims to revolutionize how oncologists detect, monitor and potentially treat cancers.  The MGH team has already developed two generations of a microfluidic chip capable of capturing CTCs with a high rate of efficiency. However the third generation technology now being developed with the companies is based on a new technological platform and will aim for even higher sensitivity, as well as suitability for broad applications and ready dissemination.

In the above demonstration of the first generation CTC-Chip, circulating tumor cells (fluorescent labeled, shown in white) mixed with blood (not labeled) are captured on nano-scale posts as they flow through the chip. The chip is the size of a microscope slide with 78,000 posts, which are coated with antibodies to epithelial cell adhesion molecules in tumor cells. (Video courtesy of Dr. Sunitha Nagrath, Massachusetts General Hospital/Harvard Medical School)

“This agreement is quite different from the usual academic-industrial agreement because we will be working together to bring new MGH-invented technology from its current, very early stage, through prototype and scale-up, to our ultimate goals of FDA approval and clinical adoption,” says Dr. Toner. “Our innovation team will be dedicated to developing this technology from its basic scientific principles all the way to initial prototyping within the biological research and clinical environments. Veridex has the knowledge required to translate early-stage technology into a product that can be reliably manufactured and meet regulatory requirements.

“Applying data gathered from CTCs to the care of cancer patients is a complex problem, and our strategy is to diversify technological approaches to find the best solutions for specific applications,” Toner adds. “We may find that different technologies work better for diagnosis, for prognosis and for the long-term goal of early detection; so we don’t want to confine ourselves to a single option.” His team is continuing to develop the microfluidic chip technology, with the support of Stand Up to Cancer.

Daniel A. Haber, M.D., Ph.D., Director, Massachusetts General Hospital Cancer Center

Daniel Haber, MD, PhD, director of the MGH Cancer Center, says, “The ability to establish a dedicated MGH research center focused on the intersection of bioengineering, molecular biology and clinical oncology presents an opportunity to develop a next-generation platform that will help us detect, define and monitor cancer cells more effectively – which should make an enormous difference in the lives of so many patients and their families.”

About Circulating Tumor Cells

Circulating tumor cells are cancer cells that have detached from the tumor and are found at extremely low levels in the bloodstream. The value of capturing and counting CTCs is evolving as more research data is gathered about the utility of these markers in monitoring disease progression and potentially guiding personalized cancer therapy.

About Veridex, LLC

Veridex, LLC, a Johnson & Johnson company, is an organization dedicated to providing physicians with high-value diagnostic oncology products. Veridex’s IVD products may significantly benefit patients by helping physicians make more informed decisions that enable better patient care. Veridex’s Clinical Research Solutions provide tools and services that may be used for the selection, identification and enumeration of targeted rare cells in peripheral blood for the identification of biomarkers, aiding scientists in their search for new, targeted therapies. For more information, visit www.veridex.com.

About Ortho Biotech Oncology Research & Development

Ortho Biotech Oncology Research & Development, a unit of Johnson & Johnson Pharmaceutical Research & Development, is a research and development organization that strives to transform cancer to a preventable, chronic or curable disease by delivering extraordinary and accessible diagnostic and therapeutic solutions that prolong and improve patients’ lives.

About Massachusetts General Hospital

Celebrating the 200th anniversary of its founding in 1811, Massachusetts General Hospital is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. For more information visit http://www.mgh.harvard.edu/.

Sources:

UH Biochemist Works To Revolutionize Ovarian Cancer Treatment By Unleashing the Power of MicroRNAs & Nanotechnology

The day when an ovarian cancer patient can treat her tumor with a single, painless pill instead of a toxic drug cocktail is the ultimate goal of the pioneering research of a University of Houston (UH) scientist.  Preethi Gunaratnee, assistant professor in the department of biology and biochemistry, is studying a class of tiny genetic molecules known as microRNAs and pinpointing those that could unleash the body’s natural cancer-fighting agents.

The day when an ovarian cancer patient can treat her tumor with a single, painless pill instead of a toxic drug cocktail is the ultimate goal of the pioneering research of a University of Houston (UH) scientist.

Preethi Gunaratnee, Ph.D., Assistant Professor, Department of Biology & Biochemistry, University of Houston

Preethi Gunaratnee, assistant professor in the department of biology and biochemistry, is studying a class of tiny genetic molecules known as microRNAs and pinpointing those that could unleash the body’s natural cancer-fighting agents. Additionally, she is developing a novel method to effectively deliver this treatment to the targeted cells by using an unusual carrier – nanoparticles of gold – through the work of Lalithya Jayarathne, a postdoctoral researcher in Gunaratne’s lab.

Gunaratne’s potentially groundbreaking work in ovarian cancer has gained exceptional notice and momentum this year with a series of high-profile research grants. In October, her ovarian cancer project was awarded a $200,000 High Impact/High Risk grant from the Cancer Prevention and Research Institute of Texas (CPRIT), which oversees the state’s billion-dollar war on cancer. In November, she was approved for a $250,000 grant from Houston’s Cullen Foundation. Earlier this year, she was chosen a beneficiary of the Baylor College of Medicine Partnership Fund.

Each year, the Baylor partnership undertakes a major fundraising campaign for a specific health project. For 2010-11, the partnership is raising money to fund the collaborative ovarian cancer project of Gunaratne and Baylor researchers Matthew Anderson, M.D., Ph.D. and Martin Matzuk, M.D., Ph.D.

All this promising research has its origins in a revolution in genetic science that began just a few years ago. Attention has long centered on nucleic acids known as DNA, with little consideration given to its cousin RNA or to microRNAs, which were considered “genetic junk” that played no significant role in the human genome, Gunaratne said.

MicroRNA Expression (Rosetta Genomics)

That began to change earlier this decade as scientists discovered that microRNAs might actually be the hidden regulators that control the 30,000 genes in the human body by silencing gene expression. Gunaratne has been at the vanguard of this development. With its 2008 acquisition of a $1 million genome sequencer device – the Illumina Genome Analyzer – UH instantly became a major player in this cutting-edge research. This state-of-the-art machine can rapidly deconstruct and analyze millions of pages worth of genetic data and allowed Gunaratne’s lab to sequence hundreds of normal and diseased tissue samples.

Gunaratne set her sights on a variety of cancers, including ovarian tumors, pediatric neuroblastoma and multiple myeloma. Using the sequencer in collaboration with Baylor, Texas Children’s Cancer Center and the Lurie Cancer Center at Northwestern University, her team created a unique database documenting genome-wide patters of microRNA and gene expression across an array of human tissues and cancers. The ultimate goal is to connect specific microRNAs with the genes they regulate, individualized to attack specific genomes.

From this database, Gunaratne’s team was able to pinpoint a handful of microRNAs in the human body that can significantly or completely suppress the growth of cancer cells. One in particular, miR-31, discovered by Baylor collaborators and Gunaratne, shows promise as a potent tumor suppressor in ovarian cancer, glioblastoma, osteosarcoma and prostate cancer.

They discovered that miR-31 can specifically target and kill cancer cells that are deficient in p53, a crucial gene that guards the integrity of the genome and prevents cancer. More than half of all cancers and 90 percent of papillary serous tumors – the most common type of malignant ovarian cancer – are p53-deficient.

In cell cultures miR-31 suppressed and killed tumor cells deficient in p53, while sparing cells with a normal p53 gene. Since all non-cancerous cells in the body would be resistant to miR-31, it can fight tumors without the side effects associated with chemotherapy.

“Delivering these microRNAs into human patients is a much trickier proposition than working on cell cultures and has never been done,” Gunaratne said. “Other types of gene therapy have been delivered with modified viruses in clinical trials, but ongoing safety concerns will likely prevent its widespread use.”

However, Gunaratne believes gold, which is biocompatible and easily functionalized to carry hundreds of microRNAs on the surface, can act as an effective carrier of genetic molecules. In lab tests, gold nanoparticles containing miR-31 penetrated 90 percent of targeted cells within 20 minutes, killing cancer cells three times faster than microRNAs delivered through lentiviruses, which are traditionally used in carrying gene-based treatments to diseased cells.

The next step is to test these microRNA-conjugated gold particles on tumors in mice to see if they can be delivered orally or through injection to shrink the tumors. If all goes as planned, this potentially revolutionary ovarian cancer treatment could be ready for phase I clinical trials in humans at the end of the two-year CPRIT grant, Gunaratne said.

Ovarian cancer is the fifth deadliest cancer among women, with about 15,000 deaths annually in the United States. Thus far, in cancer treatment generally, genetic markers have been helpful in assessing cancer patients’ risk and channeling them into the most effective treatment options. If scientists like Gunaratne are successful, doctors will go beyond just observing and reacting to a cancer patient’s gene expression to actually changing it, activating the body’s natural tumor suppressants. This could make chemotherapy a thing of the past.

“Although ovarian tumors are the focus of this project, our microRNA research is applicable to other cancers and diseases, too,” Gunaratne said. “Because a single microRNA can regulate hundreds of genes across diverse signaling pathways, they provide an especially promising way to control the patterns of gene expression that cause disease.”

Gunaratne also is a co-investigator with Baylor researchers on two other CPRIT grants announced in October, totaling $2.5 million. In one they will test siRNA-conjugated gold particles as an anti-cancer agent with Baylor’s Dr. Larry Donehower, and in the other they will use next-generation sequencing to look at epigenetic signals in malignant blood-related cancers with Dr. Margaret Goodell.

This most recent round of CPRIT grant awards marks the first time UH has received a research grant from CPRIT. Previous awards were for training graduate students and for raising cancer awareness.

“All these awards, CPRIT included, underscore UH’s growing role in biomedical research and demonstrate we can compete with other research powerhouses both locally and nationally,” Gunaratne said.

About the University of Houston

The University of Houston is a comprehensive national research institution serving the globally competitive Houston and Gulf Coast Region by providing world-class faculty, experiential learning and strategic industry partnerships. UH serves more than 38,500 students in the nation’s fourth-largest city, located in the most ethnically and culturally diverse region of the country.

About the College of Natural Sciences and Mathematics

The UH College of Natural Sciences and Mathematics, with 181 ranked faculty and approximately 4,500 students, offers bachelor’s, master’s and doctoral degrees in the natural sciences, computational sciences and mathematics. Faculty members in the departments of biology and biochemistry, chemistry, computer science, earth and atmospheric sciences, mathematics and physics conduct internationally recognized research in collaboration with industry, Texas Medical Center institutions, NASA and others worldwide.

Source: UH Biochemist Works to Revolutionize Ovarian Cancer Treatment – Preethi Gunaratne Wins Key Grants to Unleash Body’s Natural Cancer-fighting Agents, News Release, University of Houston, December 21, 2010.

Removal of Ovarian Cancer Cells From Human Ascites Fluid Using Magnetic Nanoparticles

Scientists at Georgia Tech and the Ovarian Cancer Institute have further developed a potential new treatment against cancer that uses magnetic nanoparticles to attach to ovarian cancer cells, removing them from the body. The treatment, tested in mice in 2008, has now been tested using samples from human ovarian cancer patients. The results appear online in the journal Nanomedicine.

Nanoparticles, in brown, attach themselves to ovarian cancer cells, in violet, from the human abdominal cavity. (Credit: Ken Scarberry/Georgia Tech)

Scientists at Georgia Institute of Technology (Georgia Tech) and the Ovarian Cancer Institute have further developed a potential new treatment against cancer that uses magnetic nanoparticles to attach to ovarian cancer cells, removing them from the body. The treatment, tested in mice in 2008, has now been tested using samples from human ovarian cancer patients. The results appear online in the journal Nanomedicine.

John McDonald Ph.D., Professor & Associate Dean for Biology Program Development, Georgia Institute of Technology; Chief Research Scientist, Ovarian Cancer Institute (Credit: Georgia Tech)

“We are primarily interested in developing an effective method to reduce the spread of ovarian cancer cells to other organs ,” said John McDonald, professor at the the School of Biology at the Georgia Institute of Technology and chief research scientist at the Ovarian Cancer Institute.

The idea came to the research team from the work of Ken Scarberry, then a Ph.D. student at Georgia Tech. Scarberry originally conceived of the idea as a means of extracting viruses and virally infected cells. At his advisor’s suggestion Scarberry began looking at how the system could work with cancer cells.

He published his first paper on the subject in the Journal of the American Chemical Society in July 2008. In that paper he and McDonald showed that by giving the cancer cells of the mice a fluorescent green tag and staining the magnetic nanoparticles red, they were able to apply a magnet and move the green cancer cells to the abdominal region.

Recently, McDonald and Scarberry (currently a postdoctoral fellow in McDonald’s lab) have shown that the magnetic technique works with human ovarian cancer cells.

Ken Scarberry Ph.D., Postdoctoral Fellow, McDonald Laboratory, Georgia Institute of Technology (Credit: Robert Felt, Georgia Tech.)

“Often, the lethality of cancers is not attributed to the original tumor but to the establishment of distant tumors by cancer cells that exfoliate from the primary tumor,” said Scarberry. “Circulating tumor cells can implant at distant sites and give rise to secondary tumors. Our technique is designed to filter the peritoneal fluid or blood and remove these free floating cancer cells, which should increase longevity by preventing the continued metastatic spread of the cancer.”

In tests, they showed that their technique worked as well with capturing ovarian cancer cells from human patient samples as it did previously in mice. The next step is to test how well the technique can increase survivorship in live animal models. If that goes well, they will then test it with humans.

Sources:

Novel Targeted Gene Therapies Use Diphtheria Toxin To Fight Ovarian Cancer; One Clinical Trial Underway

Two separate research teams reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer. … A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells. Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

Targeted Gene Therapy In the Fight Against Ovarian Cancer

The peritoneal cavity is a common site of ovarian cancer and accompanying ascites caused by the disease. Ascites is an abnormal buildup of fluid in the peritoneal cavity that causes swelling.  Malignant tumor cells may be found in the ascites fluid in connection with late stage ovarian cancer.  Massive ascites and the related abdominal distention can cause anorexia, nausea, vomiting and respiratory difficulties, and negatively impact the patient’s quality of life. Ovarian cancer patients frequently experience disease involvement of the pelvic and retroperitoneal lymph nodes as well. The standard primary treatment of patients with advanced stage ovarian cancer is cytoreductive surgery followed by platinum drug and taxane drug doublet chemotherapy. Despite this aggressive approach, there is a high rate of disease recurrence. Although discovery of several other active nonplatinum cytotoxic agents has improved outcome, long-term survival rates are low. Success of traditional chemotherapy has been limited by drug resistance and lack of specificity with respect to disease formation and progression. Thus, novel “targeted” ovarian cancer therapies that achieve improved long-term disease control with lower toxicity are desperately needed.

A so-called “targeted therapy” utilizes drugs or other medically manufactured substances (e.g., small molecule drugs or monoclonal antibodies) to block the growth and spread of cancer by interfering with specific molecules involved in cancer tumor growth and progression.  By identifying and selectively focusing upon molecular and cellular changes or unique genetic characteristics that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy, and less harmful to normal cells.

It is possible for a targeted therapy to incorporate a gene therapy. Gene therapy is an experimental treatment that involves the introduction of genetic material (DNA or RNA) into a human cell to fight a disease such as cancer.  When both therapeutic approaches are combined by researchers, a “targeted gene therapy” is the result.  A targeted gene therapy is an attractive approach to controlling or killing human cancer cells only if the therapy can selectively identify and exploit the genetic and epigenetic alterations in cancer cells, without harming normal cells that do not possess such alternations.

Two separate research groups reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer.  The toxin is produced by a deadly bacterium (Corynebacterium diphtheriae).  A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells.  Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

MIT-Lankenau Institute Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The MSLN & HE4 Ovarian Cancer Genes.

anderson

Daniel Anderson, Ph.D., Research Associate, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

The first study, which appears in the August 1 issue of the journal Cancer Research, was conducted by a team of researchers from the Massachusetts Institute of Technology (MIT) and the Lankenau Institute of Medical Research (Lankenau Institute). In this study, the researchers used a nanoparticle as a delivery vehicle (or vector) for DNA that encodes a diphtheria toxin suicide protein (DT-A).  The novel nanoparticles are made with positively charged, biodegradable polymers known as poly(beta-amino esters). When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can deliver functional DNA when injected into or near the targeted tissue.

The nanoparticle carrying the DT-A is designed to target overexpression of two genes (mesothelin (MSLN) and HE4 (or WFDC2)) that are highly active in ovarian tumor cells, but not in normal cells. Once inside an ovarian cancer tumor cell, the DT-A disrupts the tumor cell’s ability to manufacture critical life sustaining proteins, thereby causing cell death.  Accordingly, the choice of the DT-A fragment of a diptheria toxin gene ensures high ovarian cancer cell killing activity.  It also avoids unintended toxicity to normal cells because the DT-A released from destroyed ovarian cancer cells is not able to enter normal neighboring tissue cells in the absence of the DT-B fragment which was excluded from the original nanoparticle delivery system or vector.

As part of this study, researchers administered DT-A nanoparticles directly into the peritoneal cavity – which encases abdominal organs such as the stomach, liver, spleen, ovaries and uterus – of mice xenografted with primary and metastatic ovarian tumors.  Ovarian cancer is known to initially spread throughout the peritoneal cavity, and current therapeutic approaches in humans include direct injection into the peritoneal space, thereby targeting the therapy to the ovaries and nearby tissues where tumors may have spread.

“… [The researchers] discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. …”

langerrobert

Robert S. Langer is the David H. Koch Institute for Integrative Cancer Research Professor (there are 14 Institute Professors at MIT; being an Institute Professor is the highest honor that can be awarded to a faculty member). Dr. Langer has written approximately 1,050 articles. He also has approximately 750 issued and pending patents worldwide. Dr. Langer’s patents have been licensed or sublicensed to over 220 pharmaceutical, chemical, biotechnology and medical device companies. He is the most cited engineer in history.

Sawicki

Janet Sawicki, Ph.D., Professor, Lankenau Institute of Medical Research. Dr. Sawicki also serves as an Associate Professor at the Kimmel Cancer Center of Thomas Jefferson University. Her ovarian cancer research is funded by the National Institutes of Health, the U.S. Department of Defense, the Sandy Rollman Foundation, the Teal Ribbon Ovarian Cancer Foundation, and the Kaleidoscope of Hope Foundation.

Daniel Anderson, Ph.D., research associate in the David H. Koch Institute for Integrative Cancer Research at MIT and a senior author of the paper, and others from MIT, including Institute Professor Robert Langer, along with researchers from the Lankenau Institute, led by Professor Janet Sawicki, discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. Furthermore, the novel therapy did not have the toxic side effects of chemotherapy because the diptheria toxin gene is engineered to function in ovarian cells but is inactive in normal cell types.

Based upon these finding, the MIT and Lankenau Institute researchers concluded that IP administration of DT-A nanoparticles, combined with designed targeting of those nanoparticles against ovarian tumor cell gene (MSLN & HE4) expression, holds promise as an effective therapy for advanced-stage ovarian cancer. According to Anderson, human clinical trials could start, after some additional preclinical studies, in about 1 to 2 years.  Currently ovarian cancer patients undergo surgery followed by chemotherapy. In many cases, the cancer returns after treatment.  Disease recurrence is problematic because there are no curative therapies for advanced-stage tumors.

For several years, the MIT-Lankenau Institute team worked to develop the DT-A nanoparticles as an alternative to viruses, which are associated with safety risks. In addition to ovarian cancer, these nanoparticles have demonstrated treatment potential for a variety of diseases, including prostate cancer and viral infection. “I’m so pleased that our research on drug delivery and novel materials can potentially contribute to the treatment of ovarian cancer,” Langer said. In future studies, the team plans to examine the effectiveness of nanoparticle-delivered diphtheria toxin genes in other types of cancer, including brain, lung and liver cancers.

Other MIT authors of the paper are recent MIT Ph.D. recipients Gregory Zugates and Jordan Green (now a professor at John’s Hopkins University), and technician Naushad Hossain. The research was funded by the Department of Defense and the National Institutes of Health.

Israeli Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The H19 Ovarian Cancer Gene.

The second study was conducted by Israeli researchers and was published August 6 online ahead of print in the Journal of Translational Medicine.

In the provisional study report, the researchers note that based upon earlier studies from their team and others, the H19 gene has emerged as a candidate for cancer gene therapy. The H19 gene is expressed at substantial levels in ovarian cancer tumor cells, but is nearly undetectable in surrounding normal tissue cells.  Although the Israeli research team acknowledges that the exact function of H19 is the subject of past debate, it notes that recent data suggests a role for H19 in promoting cancer progression, angiogenesis and metastasis.

As a first step, Israeli researchers tested H19 gene expression in ovarian cancer cells obtained from the ascites fluid of 24 patients, and established that H19 expression levels were detected in 90% of the tested patients. Of those patients with positive H19 expression, 76% showed a moderate or high level of expression, while 24% showed a low level of expression.

Next, the researchers created a DT-A nanoparticle similar to the one created by the MIT/Lankenau research team as described above, except the Israeli nanoparticle was designed to target H19 overexpression within ovarian cancer cells.  The therapeutic effect of the DT-A/H19 nanoparticles was first tested in vitro against various ovarian cancer cell lines and cells obtained from patient ascites fluid.  The researchers determined that the DT-A/H19 nanoparticle therapy caused ovarian cancer cell death.  The therapeutic effect of the DT-A nanoparticles was tested in vivo by injecting the DT-A nanoparticles into mice xenografted with ovarian cancer tumors. The researchers estimate that the DT-A nanoparticle therapy reduced ovarian cancer tumor growth in the treated mice by 40%.

Based upon these finding, the researchers note that although the study report issued is provisonal, it is their working hypothesis that intraperitoneal administration of DT-A/H19 nanoparticles holds the potential to (1) reach ascites tumor cells, (2) deliver its intracellular toxin without targeting normal tissue cells, and (3) reduce tumor burden & fluid accumulation; and therefore, improve the patient’s quality of life, and hopefully, prolong her survival.

  • DT-A/H19 Nanoparticle Therapy Administered To An Israeli Patient On A Compassionate Use Trial Basis

In the provisional study report, the researchers state that the targeted gene therapy was administered to an Israeli patient with advanced, recurrent ovarian cancer, who qualified for compassionate use treatment under Israeli regulatory rules.  Specifically, the patient’s intraperitoneal ovarian cancer metastases and ascites were treated with the DT-A/H19 nanoparticle therapy after the failure of conventional chemotherapy. The results of the single patient compassionate use trial suggest that the drug caused no serious adverse events at any drug dosage level.  Moreover, the patient experienced (1) a 50% decrease in serum cancer marker protein CA-125, (2) a significant decrease in the number of cancerous cells in the ascites, and (3) a clinical improvement as reported by her doctors.  It is reported that the patient’s quality of life increased during the course of treatment and her condition continues to be stable, with no new cancerous growths.

  • Phase I/II Clinical Trial To Test DT-A/H19 Nanoparticle Therapy (BC-819) In the U.S. & Israel

The DT-A/H19 nanoparticle therapy is being developed commercially by BioCancell Therapeutics, Inc (BioCancell) Recently, BioCancell announced the opening of a clinical trial to test the DT-A/H19 nanoparticle therapy (also referred to as BC-819) in patients with advanced stage ovarian cancer.  The clinical trial is entitled, Phase 1/2a, Dose-Escalation, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Intraperitoneal Administration of DTA-H19 in Subjects With Advanced Stage Ovarian Cancer, and the trial investigators are recruiting patients in the U.S. and Israel as indicated below.

University of Pennsylvania Medical Center [Abramson Cancer Center] (Recruiting)
Philadelphia, Pennsylvania, United States, 19104-6142
Contact: Lana E. Kandalaft, Pharm.D, PhD – 215-537-4782 (lknd@mail.med.upenn.edu)
Principal Investigator: George Coukos, M.D., Ph.D.

Massey Cancer Center (Not yet recruiting)
Richmond, Virginia, United States, 23298-0037
Contact: Jane W. Baggett, RN 804-628-2360 (jbaggett@mcvh-vcu.edu)
Principal Investigator: Cecelia H. Boardman, M.D.

The Edith Wolfson Medical Center (Recruiting)
Holon, Israel
Contact: Pnina Nir (972)-52-8445143 (pninanir@wolfson.health.gov.il)
Principal Investigator: Tally Levy, M.D.

Hadassah University Hospital (Recruiting)
Jerusalem, Israel
Contact: Zoya Bezalel (972)-2-6776725 (zoyab@hadassah.org.il)
Principal Investigator: David Edelman, MD

Meir Hospital (Recruiting)
Kfar Saba, Israel
Contact: Tal Naderi 09-7472213 (Ta.INadiri@clalit.org.il)
Principal Investigator: Ami Fishman, MD

In the provisional study report, the Israeli researchers discuss the importance of collecting data regarding the correlation between the level of ovarian cancer cell H19 expression and the efficacy of the treatment as part of the clinical trial discussed above.  Based upon accrued future clinical trial data, the researchers believe that they will be able to identify in advance patients that will respond to this novel therapy, as well as non-responders who are resistant to all known therapies, thereby avoiding treatment failure and unnecessary suffering and cost.

References:

Trojan Horse* For Ovarian Cancer–Nanoparticles Turn Immune System Soldiers Against Tumor Cells

In a feat of trickery, Dartmouth Medical School immunologists have devised a Trojan horse to help overcome ovarian cancer, unleashing a surprise killer in the surroundings of a hard-to-treat tumor. Using nanoparticles–ultra small bits– the team has reprogrammed a protective cell that ovarian cancers have corrupted to feed their growth, turning the cells back from tumor friend to foe. Their research, published online July 13 for the August Journal of Clinical Investigation, offers a promising approach to orchestrate an attack against a cancer whose survival rates have barely budged over the last three decades …

Hanover, N.H.—In a feat of trickery, Dartmouth Medical School immunologists have devised a Trojan horse to help overcome ovarian cancer, unleashing a surprise killer in the surroundings of a hard-to-treat tumor.

Using nanoparticles–ultra small bits– the team has reprogrammed a protective cell that ovarian cancers have corrupted to feed their growth, turning the cells back from tumor friend to foe. Their research, published online July 13 for the August Journal of Clinical Investigation, offers a promising approach to orchestrate an attack against a cancer whose survival rates have barely budged over the last three decades.

Dr. Jose Conejo-Garcia (right) with graduate student Juan Cubillos-Ruiz  (Photo Source:  Dartmouth Medical School News Release,

Dr. Jose Conejo-Garcia (right) with graduate student Juan Cubillos-Ruiz (Photo Source: Dartmouth Medical School News Release, 13 Jul. 09)

“We have modulated elements of the tumor microenvironment that are not cancer cells, reversing their role as accomplices in tumor growth to attackers that boost responses against the tumor,” said Dr. Jose Conejo-Garcia, assistant professor of microbiology and immunology and of medicine, who led the research. “The cooperating cells hit by the particles return to fighters that immediately kill tumor cells.”

The study, in mice with established ovarian tumors, involves a polymer now in clinical trials for other tumors. The polymer interacts with a receptor that senses danger to activate cells that trigger an inflammatory immune response.

The Dartmouth work focuses on dendritic cells–an immune cell particularly abundant in the ovarian cancer environment. It does take direct aim at tumor cells, so it could be an amenable adjunct to other current therapies.

“The cooperating cells hit by the particles return to fighters that immediately kill tumor cells.” —Dr. Jose Conejo-Garcia

“That’s the beautiful part of story–people usually inject these nanoparticles to target tumor cells. But we found that these dendritic cells that are commonly present in ovarian cancer were preferentially and avidly engulfing the nanoparticles. We couldn’t find any tumor cells taking up the nanoparticles, only the dendritic cells residing in the tumor,” explained Juan R. Cubillos-Ruiz, graduate student and first author.

Dendritic cells are phagocytes–the soldiers of the immune system that gobble up bacteria and other pathogens, but ovarian cancer has co-opted them for its own use, he continued. “So we were trying to restore the attributes of these dendritic cells–the good guys; they become Trojan horses.”

Cancer is more than tumor cells; many other circulating cells including the dendritic phagocytes converge to occupy nearby space. The dendritic cells around ovarian cancer scoop up the nanocomplexes, composed of a polymer and small interfering RNA (siRNA) molecules to silence their immunosuppressive activity.

Nanoparticle incorporation transforms them from an immunosuppressive to an immunostimulatory cell type at tumor locations, provoking anti-tumor responses and also directly killing tumor cells. The effect is particularly striking with an siRNA designed to silence the gene responsible for making an immune protein called PD-L.

The new findings also raise a warning flag about the use of gene silencing complexes in cancer treatment. Inflammation is a helpful immune response, but the researchers urge caution when using compounds that can enhance inflammation in a patient already weakened by cancer.

Ovarian cancer, which claims an estimated 15,000 US lives a year, is an accessible disease for nanoparticle delivery, according to the investigators. Instead of systemic administration, complexes can be put directly into the peritoneal cavity where the phagocytes take them up.

Samples of human ovarian cancer cells show similar responses to nanoparticle stimulation, the researchers observed, suggesting feasibility in the clinical setting. It could be part of a “multimodal approach,” against ovarian cancer, said Conejo-Garcia also a member of the Dartmouth’s Norris Cotton Cancer Center. “The prevailing treatment is surgical debulking, followed by chemotherapy. Our findings could complement those because they target not the tumor cells themselves, but different cells present around the tumor.”

Co-authors are Xavier Engle, Uciane K. Scarlett, Diana Martinez, Amorette Barber, Raul Elgueta, Li Wang, Yolanda Nesbeth and Charles Sentman of Dartmouth; Yvon Durant of University of New Hampshire, Andrew T Gewirtz of Emory, and Ross Kedl of University of Colorado.

The work was supported by grants from the National Institutes of Health, including the National Cancer Institute and National Center for Research Resources, a Liz Tilberis Award from the Ovarian Cancer Research Fund, and the Norris Cotton Cancer Center Nanotechnology Group Award.

Read an interview of Jose Conejo – Garcia with the Ovarian Cancer Research Fund.

Source: Trojan Horse for Ovarian Cancer–Nanoparticles Turn Immune System Soldiers against Tumor Cells, News Release, Dartmouth Medical School, July 13, 2009 (summarizing Cubillos-Ruiz JR, Engle X, Scarlett UK, et. al. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest. 2009 Aug 3;119(8):2231-2244. doi: 10.1172/JCI37716. Epub 2009 Jul 13).

__________________

* The Trojan Horse was a tale from the Trojan War, as told in Virgil’s Latin epic poem The Aeneid. The events in this story from the Bronze Age took place after Homer’s Iliad, and before Homer’s Odyssey. It was the strategy that allowed the Greeks finally to enter the city of Troy and end the conflict. In the best-known version, after a fruitless 10-year siege of Troy, the Greeks built a huge horse figure and hid a select force of men within it. The Greeks left the Horse at the city gates of Troy and pretended to sail away.  Thereafter, the Trojans pulled the Horse into their city as a victory trophy. That night the Greek force crept out of the Horse and opened the gates for the returning Greek army, which had sailed back to Troy under cover of night. The Greek army entered and destroyed the city, decisively ending the war. A “Trojan Horse” has come to mean any trick that causes a target to invite a foe into a securely protected bastion or place.