Preclinical Results Validate Lpathomab As A Potential Future Treatment for Ovarian Cancer

“Lpath, Inc. … , the category leader in bioactive-lipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies …”

“Lpath Presents Compelling New Preclinical Results of Its Anti-Cancer Drug Candidate, Lpathomab(TM), at the AACR 100th Annual Meeting –

New In Vivo and In Vitro Results Provide Further Validation of Lpathomab as Potential Treatment for Cancer

SAN DIEGO, CA, Apr 20, 2009 (MARKET WIRE via COMTEX)Lpath, Inc. (OTCBB: LPTN), the category leader in bioactivelipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies. The results were presented today by Lpath scientists at the 100th Annual Meeting of the American Association for Cancer Research (AACR) in Denver, Colorado.

Lpathomab is a monoclonal antibody that binds to the bioactive lipid lysophosphatidic acid (LPA) and acts as a molecular sponge to absorb LPA, thereby neutralizing LPA-mediated biological effects on tumor growth, angiogenesis, and metastasis. LPA has been associated with a variety of cancer types, but the correlation with ovarian cancer and breast cancer has been particularly strong.

Using the human ovarian cell line called SKOV3, Lpath’s preclinical studies demonstrated Lpathomab significantly reduced IL-8 and IL-6 cytokine release in SKOV3-conditioned media and blocked tumor-cell migration triggered by LPA (both IL-8 and IL-6 promote tumor angiogenesis and metastasis). More important, Lpathomab inhibited the progression of SKOV3 tumor cells when injected into the peritoneal cavity of mice and reduced levels of pro-metastatic factors in these animals.

Lpathomab also reduced neovascularization (new blood-vessel growth) in two classical angiogenic models and showed preliminary anti-metastatic activity when tested in a classical experimental metastasis model.

According to Roger Sabbadini, Ph.D., Lpath’s founder and chief scientific officer, ‘In view of these promising preclinical results, we believe Lpathomab has the potential to augment the efficacy of current ovarian cancer therapy by blocking the growth-promoting, angiogenic, and metastatic effects of LPA.’

About Lpath

San-Diego-based Lpath, Inc. is the category leader in bioactive-lipid-targeted therapeutics, an emerging field of medical science whereby bioactive signaling lipids are targeted for treating important human diseases. ASONEP(TM), an antibody against Sphingosine-1-Phosphate (S1P), is currently in a Phase 1 clinical trial in cancer patients and also holds promise against multiple sclerosis and various other disorders. ASONEP is being developed with the support of partner Merck-Serono as part of a worldwide exclusive license. A second product candidate, iSONEP(TM) (the ocular formulation of the S1P antibody), has demonstrated superior results in various preclinical models of age-related macular degeneration (AMD) and retinopathy and is in a Phase 1 clinical trial in wet-AMD patients. Lpath’s third product candidate, Lpathomab(TM), is an antibody against lysophosphatidic acid (LPA), a key bioactive lipid that has been long recognized as a valid disease target (cancer, neuropathic pain, fibrosis). The company’s unique ability to generate novel antibodies against bioactive lipids is based on its ImmuneY2(TM) drug-discovery engine, which the company is leveraging as a means to expand its pipeline. For more information, visit www.Lpath.com …”

Sources:

Novogen’s NV-128 Targets mTOR Pathway To Block Differentiation and Induce Cell Death in Ovarian Cancer Stem Cells

“Data just presented at the Annual Meeting of the American Association for Cancer Research in Denver has demonstrated that NV-128, a Novogen, Limited (ASX: NRT NASDQ: NVGN) synthetic isoflavonoid compound, not only induces cell death in Ovarian Cancer Stem Cells (OCSCs), but also blocks their differentiation into structures which are required to support tumor growth.  In a poster presentation by Ayesha Alvero, MD, of Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Science, it was revealed that in addition to an inhibitory effect on OCSC growth, NV-128 displays a remarkable ability to inhibit differentiation of OCSCs into formation of new blood vessels. … ‘We have now demonstrated that by inhibiting the mTOR pathway in both the cancer stem cells and the mature cancer cells, we are able to inhibit development of structural elements necessary for tumor development as well as limit the number of cancer cells,’ Professor Mor said. ‘These results open a new avenue for the development of better treatment modalities for ovarian cancer patients.’ …”

“(Sydney Australia and New Canaan, Connecticut – 20 April, 2009) – Data just presented at the Annual Meeting of the American Association for Cancer Research in Denver has demonstrated that NV-128, a Novogen, Limited (ASX: NRT NASDQ: NVGN) synthetic isoflavonoid compound, not only induces cell death in Ovarian Cancer Stem Cells (OCSCs), but also blocks their differentiation into structures which are required to support tumor growth.

alvero

Ayesha Alvero, M.D., Associate Research Fellow, Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine

In a poster presentation by Ayesha Alvero, MD, of Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Science, it was revealed that in addition to an inhibitory effect on OCSC growth, NV-128 displays a remarkable ability to inhibit differentiation of OCSCs into formation of new blood vessels.

The anti-proliferative effects were demonstrated to be achieved as a result of NV-128 inhibiting phosphorylation of the pro-survival mTOR pathway resulting in mitochondrial depolarisation and cell death. Time lapsed photographic morphometry revealed in graphic detail how NV-128 induces morphological changes in OCSCs after 24 hours, even when dosed as low as 1μg/ml with a progressive “clearing” of cytoplasm and condensation of nuclear material.

The effect of NV-128 on OCSC vessel formation was observed by plating OCSCs in high-density matrigel either without NV-128 (controls) or in the presence of 0.1 mg/ml NV-128 and observing for 48 hours. Whereas the control cultures showed differentiation of the stem cells into endothelial-type cells forming structurally intact blood vessels in the culture plates, cells cultured in the presence of NV-128 showed no differentiation and no structural elements were observed.

OCSCs represent a highly chemo-resistant cell population, allowing them to survive conventional chemotherapy. Thus these cells are considered to be the potential source of tumor induction and post-treatment recurrence.

The team from Yale University, headed by Professor Gil Mor, recently reported the identification and characterisation of OCSCs using the CD44 marker and demonstrated pronounced up-regulation of the mTOR survival pathway in these cells. They previously reported that NV-128 is able to specifically induce mTOR dephosphorylation resulting in inhibition of both mTORC1 and mTORC2 activity in mature ovarian cancer cells derived from established human cancers and cultured in vitro. In mice with human ovarian cancers established by grafting techniques (xenografts) NV-128 caused substantial cancer cell death, reducing tumor growth with no apparent toxic side-effects.

mor

Gil Mor, M.D., Ph.D., Associate Professor, Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine

‘We have now demonstrated that by inhibiting the mTOR pathway in both the cancer stem cells and the mature cancer cells, we are able to inhibit development of structural elements necessary for tumor development as well as limit the number of cancer cells,’ Professor Mor said. ‘These results open a new avenue for the development of better treatment modalities for ovarian cancer patients.’

‘We are encouraged by these data from animal studies showing a combination of anti-cancer activities of NV-128, coupled with an apparently high safety profile,’ said Professor Alan Husband, Group Director of Research for the Novogen group. ‘This anti-angiogenic effect, coupled with the absolute effects on cell survival, demonstrate the potential for NV-128 to become a powerful new tool in prevention as well as treatment of cancer.’

Novogen has previously reported on the parallel effects of NV-128 in non-small cell lung cancer models and the Company intends to pursue this, as well as ovarian cancer, as target indications.

Novogen is currently in advanced negotiations with its majority owned subsidiary, Marshall Edwards, Inc. (MEI), to out-license NV-128 to MEI for its clinical development as a potential cancer therapeutic. To view an online abstract relating to this study, [CLICK HERE].

About NV-128

NV-128 does not rely on the traditional approach of caspase-mediated apoptosis, a death mechanism which is not effective in cancer cells that have become resistant to chemotherapy. Rather, NV-128 uncouples a signal transduction cascade which has a key role in driving protein translation and uncontrolled cancer cell proliferation. Further, NV-128 induces mitochondrial depolarisation via the novel mTOR pathway. In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies. Inhibition of the mTOR pathway appears to shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells. Animal studies have shown that NV-128 not only significantly retards tumor proliferation, inhibiting the progression of ovarian cancers-engrafted into mice, but produces this effect without apparent toxicity. This effect was shown to be due to caspase-independent pathways involving inhibition of the mTOR pathway. Unlike analogues of rapamycin, which target only mTORC1, NV-128’s capacity to inhibit mTOR phosphorylation enables it to inhibit both mTORC1 and mTORC2 activity. This blocks growth factor-driven activation of AKT and the potential for development of chemoresistance.

About Novogen Limited

Novogen Limited (ASX: NRT; NASDAQ: NVGN) is an Australian biotechnology company based in Sydney, Australia, that is developing a range of oncology therapeutics from its proprietary flavonoid synthetic chemistry technology platform. More information on NV-128 and on the Novogen group of companies can be found at www.novogen.com.

Sources:

Additional Information Re Novogen’s NV-128:

Personalized Medicine Helps Breast, Colorectal & Ovarian Cancer Patients Survive

“Cancer patients can survive longer under treatments based on their individual genetic profiles, according to a nationwide study released jointly today by Phoenix-area healthcare organizations. The study shows that molecular profiling of patients can identify specific treatments for individuals, helping keep their cancer in check for significantly longer periods, and in some cases even shrinking tumors. Study results were released today at the 100th annual meeting of the American Association for Cancer Research in Denver by Dr. Daniel Von Hoff, Physician-In-Chief of the Phoenix-based Translational Genomics Research Institute (TGen), and the study’s Principal Investigator. … Patients experienced varying levels of improvement. Among those with breast cancer, the period of progression-free survival increased for 44 percent of patients; for colorectal, 36 percent of patients; for ovarian, 20 percent of patients; and for miscellaneous cancers the improvement was seen in 16 percent of patients. …” [Emphasis added by Libby’s H*O*P*E*™]


tgen-logo1

“Personalized medicine helps cancer patients survive – TGen, Scottsdale Healthcare and Caris Dx clinical trial shows molecular profiling can result in specific treatments for individual patients that significantly limit the growth and spread of tumors

PHOENIX, Ariz. – April 19, 2009 – Cancer patients can survive longer under treatments based on their individual genetic profiles, according to a nationwide study released jointly today by Phoenix-area healthcare organizations.

The study shows that molecular profiling of patients can identify specific treatments for individuals, helping keep their cancer in check for significantly longer periods, and in some cases even shrinking tumors.

von_hoff

Daniel Von Hoff, M.D., F.A.C.P., Physician in Chief & Senior Investigator, The Translational Genomics Research Institute; Chief Scientific Officer, TGen Clinical Research Services, Scottsdale Healthcare; Clinical Professor of Medicine, University of Arizona Department of Medicine

Study results were released today at the 100th annual meeting of the American Association for Cancer Research in Denver by Dr. Daniel Von Hoff, Physician-In-Chief of the Phoenix-based Translational Genomics Research Institute (TGen), and the study’s Principal Investigator.

The study included 66 patients at nine centers across the United States, including Scottsdale Heathcare. Dr. Von Hoff also is the Chief Scientific Officer of TGen Clinical Research Services (TCRS) at Scottsdale Healthcare, a partnership between TGen and Scottsdale Healthcare that is administered by the Scottsdale Clinical Research Institute (SCRI) at Scottsdale Healthcare.

All of the patients had previously experienced growth of their tumors while undergoing as many as two to six prior cancer treatments, including conventional chemotherapy.

However, after molecular profiling identified precise targets, new treatments were administered that resulted in patients experiencing significant periods of time when there was no progression of their cancer.

This clinical trial was unique because patients acted as their own control,’ said Dr. Von Hoff. ‘We compared each patient’s progression-free survival, following treatment based on molecular profiling, to how their tumors progressed under their prior treatment regimens, before molecular profiling.’

In a significant number of patients, the targeted treatments provided significantly longer periods when tumors did not progress, or even shrunk, said Dr. Von Hoff, who also is a Medical Director of US Oncology and a former Director of the Arizona Cancer Center at the University of Arizona.

Dr. Von Hoff said the new study was done in a way that avoided issues surrounding tumor subtypes and differences in individual biology, which have confounded other clinical trials.

He said this clinical trial demonstrated the value of personalized medicine, in which treatments are prescribed based on an individual’s specific genetic makeup. The type of drugs, dosages, their delivery and other treatment aspects – all are based on each patient’s individual medical needs.

Among the patients, 27 percent had breast cancer, 17 percent had colorectal cancer, 8 percent had ovarian cancer and 48 percent had cancers that were classified as miscellaneous.

Patients experienced varying levels of improvement. Among those with breast cancer, the period of progression-free survival increased for 44 percent of patients; for colorectal, 36 percent of patients; for ovarian, 20 percent of patients; and for miscellaneous cancers the improvement was seen in 16 percent of patients.

‘With this trial, we are showing the power of personalized medicine using the tools we already have available to us. As these tools become more precise and more effective, the value of personalized medicine will increase,’ Dr. Von Hoff said.

The molecular profiling for this research study was performed by Caris Diagnostics (Caris Dx) in Phoenix.

These results are the first in a series of studies in support of Target NowTM, a commercially-available oncology testing service offered exclusively by Caris Dx. Target Now uses cutting-edge molecular profiling techniques, including both DNA microarray and immunohistochemical (IHC) analysis, to provide individualized information about a patient’s tumor as an aid to the treating oncologist.

‘This trial is evidence of an important breakthrough in the treatment of cancer. We are excited to work with Dr. Von Hoff and TGen as we make this important molecular diagnostic information available to physicians to aid in therapy-selection decision making,’ said David D. Halbert, Chairman and CEO of Caris Diagnostics. ‘The valuable information provided through the Target Now panel of tests improves patient care while reducing costs for the payer.’

Clinical studies were conducted by TCRS at the Virginia G. Piper Cancer Center at Scottsdale Healthcare Shea Medical Center. Scottsdale Healthcare is a primary clinical research site for TGen.

‘Patients in our community have access to ground-breaking, world-class research right in their own backyard thanks to this collaboration,’ said Tom Sadvary, president and CEO of Scottsdale Healthcare. ‘Our goal is reducing the time it takes to get new treatment discoveries from the research lab to the patient. We are thrilled to see these advances in personalized medicine taking place right here in Scottsdale.’

The recent clinical study was dubbed the Bisgrove Trial, after longtime Scottsdale Healthcare supporter Jerry Bisgrove. The trial was funded through a $5 million grant from Mr. Bisgrove’s Stardust Foundation to the Scottsdale Healthcare Foundation. Mr. Bisgrove has been a patient at Scottsdale Healthcare and is a member of the Scottsdale Healthcare Foundation Board of Trustees. In honor of the Stardust gift, the research building at the Virginia G. Piper Cancer Center at Scottsdale Healthcare Shea Medical Center is named the Debi and Jerry Bisgrove Research Pavilion.

‘The Stardust Foundation is proud to have played a key role in the advancements in cancer research represented by Dr. Von Hoff’s clinical trial. We believe we are closer than ever to finding a cure for this devastating disease that affects so many millions,’ Mr. Bisgrove said.

*          *          *

About Scottsdale Healthcare
Scottsdale Healthcare is a primary clinical research site for TGen. TGen Clinical Research Services (TCRS) at Scottsdale Healthcare is housed in the Virginia G. Piper Cancer Center at Scottsdale Healthcare, located on the Scottsdale Healthcare Shea medical campus. Scottsdale Healthcare is the not-for-profit parent organization of the Scottsdale Healthcare Shea, Scottsdale Healthcare Osborn and Scottsdale Healthcare Thompson Peak hospitals, Virginia G. Piper Cancer Center, Scottsdale Clinical Research Institute, TGen Clinical Research Services at Scottsdale Healthcare, Scottsdale Healthcare Home Health Services, Scottsdale Healthcare Community Health Services, and Scottsdale Healthcare Foundation. For additional information, visit www.shc.org.

About Scottsdale Clinical Research Institute (SCRI)
SCRI, established in 2005, provides infrastructure and support for the clinical research at Scottsdale Healthcare. Start-up funding for SCRI was provided by a lead gift of $4.5 million from the Virginia G. Piper Charitable Trust in 2005. An additional $5 million was provided by the Stardust Foundation to support this multi-site molecular profiling study of targeted therapies for treatment refractory cancers coordinated by SCRI. A defining feature of SCRI is a focus on genomics and personalized medicine as well as clinical and translational research. The basic science arm of SCRI is provided by a partnership with the Translational Genomics Research Institute (TGen). Innovations from TGen’s laboratory are taken to the bedside at SHC by our joint clinical research program, TGen Clinical Research Services (TCRS) at Scottsdale Healthcare. Additional research collaborations include the University of Arizona, Arizona State University, other local health care delivery systems and participation in the Arizona NIH Clinical and Translational Science Award (CTSA) program initiative. Areas of study at SCRI include Cancer, Cardiovascular, Trauma, Metabolic and Nanomedicine.

Press Contact:
Keith Jones
Public Relations Director
Scottsdale Healthcare
480-882-4412
kjones@shc.org

About TGen
The Translational Genomics Research Institute (TGen) is a non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
syozwiak@tgen.org

About Caris Diagnostics
Caris Diagnostics (Caris Dx) is a leading provider of the highest quality diagnostic, translational development and pharmaceutical services encompassing anatomic pathology and molecular testing. Caris Diagnostics provides world-class pathology services to physicians who treat patients in the community setting. The company provides academic-caliber medical consults through its industry-leading team of subspecialty fellowship and expert-trained pathologists in gastrointestinal and liver pathology, dermatopathology and hematopathology. Caris Diagnostics provides the highest levels of service to its customers and their patients through its state-of-the-art laboratories; proprietary, advanced clinical and technology solutions; and rigorous quality assurance programs. Through the molecular testing expertise of the Caris Molecular Profiling Institute (Caris MPI) at Caris Dx, the company also offers advanced molecular analyses of patient samples through prognostic testing services and genomic and proteomic profiling to provide critical information to physicians treating cancer and other complex diseases. In addition, Caris MPI supports pharmaceutical companies and other researchers in their clinical trials for targeted therapeutics with custom genomic and proteomic analyses, analyte preservation, tissue procurement and comprehensive reporting services. The company has strategic relationships with the International Genomics Consortium, US Oncology, the Translational Genomics Research Institute, and the Biodesign Institute of Arizona State University. More than 2,000 physicians nationally use Caris Diagnostics. Formed in 1996, the company is headquartered in Irving, Texas and operates four laboratories: Irving, Texas; Phoenix, Arizona (2 sites); Newton, Massachusetts. Additional information is available at www.carisdx.com.

Press Contact:
Brian Wright
Caris Dx
(602) 358-8916
bwright@carismpi.com”

Sources:

Genetic Variations In miRNA Processing Pathway & Binding Sites Help Predict Ovarian Cancer Risk

“Genetic variations in the micro-RNA (miRNA) processing pathway genes and miRNA binding sites predict a woman’s risk for developing ovarian cancer and her prospects for survival, researchers from The University of Texas M. D. Anderson Cancer Center reported at the 100th annual meeting of the American Association for Cancer Research. … The unique study was the first to examine the association of genetic variants related to miRNA with ovarian cancer risk, overall survival for ovarian cancer patients, and platinum-based chemotherapy response. …”

Genetic variations in miRNA processing pathway and binding sites help predict ovarian cancer risk – Several variations indicate likelihood of response to platinum-based chemotherapy

DENVER – Genetic variations in the micro-RNA (miRNA) processing pathway genes and miRNA binding sites predict a woman’s risk for developing ovarian cancer and her prospects for survival, researchers from The University of Texas M. D. Anderson Cancer Center reported at the 100th annual meeting of the American Association for Cancer Research.

wu

Xifeng Wu, M.D., Ph.D., Professor, Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center

‘We found a gene dosage effect, the more unfavorable variations a woman has, the greater her ovarian cancer risk and the shorter her survival time,’ said senior author Xifeng Wu, M.D., Ph.D., professor in M. D. Anderson’s Department of Epidemiology. Median survival, for example, ranged from 151 months for women with fewest unfavorable variations to 24 months for those with the most.

Several variations also indicate likely response to platinum-based chemotherapy.

‘Our findings have the potential clinical application of indicating a patient’s prognosis and showing who will respond to different therapies by analyzing a single blood sample,’ Wu said. ‘We also will incorporate this genetic information with epidemiological information to build a comprehensive model to predict susceptibility to ovarian cancer.’

The team chose the miRNA processing pathway because it is crucial to production of miRNAs, the small molecules that regulate between one third and half of all genes. The researchers also chose the binding sites on host genes where miRNAs exert their effects on gene expression.

They analyzed 219 potential functional single nucleotide polymorphisms (SNPs) – variations of a single DNA building block in a gene – in eight genes that process miRNA and at the miRNA binding sites of 129 cancer-relevant genes. The study examined genetic information from 417 cancer patients and 417 healthy controls. To minimize the possible confounding effects of ethnicity, 339 Caucasian cases and 349 controls were analyzed.

They discovered 12 SNPs to be significantly associated with ovarian cancer risk. Moreover, compared to women with five or fewer unfavorable genotypes, women with eight or more of these unfavorable genotypes were 4.5 times more likely to develop ovarian cancer and women with six to eight unfavorable SNPs were at twice the risk.

The team also found 21 SNPs significantly associated with overall survival. Median survival was 151 months for women with six or fewer unfavorable variations; 42 months for those with seven to nine unfavorable variations; and 24 months for those with 10 or more. One of the outcome risk SNPs also was strongly associated with platinum-based chemotherapy response, with those having the SNP 3.4 times less likely to respond to chemotherapy.

Wu collaborated with Dong Liang, Ph.D, in the College of Pharmacy and Health Sciences, Texas Southern University, and Karen Lu, M.D., professor in M. D. Anderson’s Department of Gynecologic Oncology, on this study.

The unique study was the first to examine the association of genetic variants related to miRNA with ovarian cancer risk, overall survival for ovarian cancer patients, and platinum-based chemotherapy response. Such a wide-ranging inquiry was made possible by M. D. Anderson’s extensive clinical and genetic data sets, Wu said.

Co-authors with Wu, first author Liang, Ph.D., and Lu are; Jie Lin, Ph.D., Xia Pu, Yuanqing Ye, Ph.D., all in the Department of Epidemiology; and Larissa Meyer, M.D., in the Department of Gynecologic Oncology at M. D. Anderson Cancer Center. Pu is a graduate student at The University of Texas Graduate School of Biomedical Sciences at Houston, which is a joint effort of M. D. Anderson and The University of Texas Health Science Center at Houston.

This research was supported by an award by the Department of Defense Ovarian Cancer Research Program.”

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

Sources:

Addition of Dasatinib (Sprycel) to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancers

“The addition of a chemotherapeutic drug for leukemia to a standard regimen of two other chemotherapy drugs appears to enhance the response of certain ovarian cancers to treatment, according to a pre-clinical study led by researchers in the Duke Comprehensive Cancer Center.  ‘We know that a pathway called SRC is involved in cell proliferation in certain types of cancers, including some ovarian cancers,’ said Deanna Teoh, MD, a fellow in gynecologic oncology at Duke and lead investigator on this study.  ‘By examining gene expression data, we determined that the combination of the leukemia drug dasatinib (Sprycel) made carboplatin and paclitaxel more effective in cell lines with higher levels of SRC expression and SRC pathway deregulation.’ …”

secord3

Angeles Secord, MD, Gynecologic Oncologist, Duke University Medical Center & Senior Investigator on this study. Deanna Teoh, MD, Gynecologic Oncologist at Duke was the lead investigator.

“The addition of a chemotherapeutic drug for leukemia to a standard regimen of two other chemotherapy drugs appears to enhance the response of certain ovarian cancers to treatment, according to a pre-clinical study led by researchers in the Duke Comprehensive Cancer Center.

‘We know that a pathway called SRC is involved in cell proliferation in certain types of cancers, including some ovarian cancers,’ said Deanna Teoh, MD, a fellow in gynecologic oncology at Duke and lead investigator on this study.

‘By examining gene expression data, we determined that the combination of the leukemia drug dasatinib (Sprycel®) made carboplatin and paclitaxel more effective in cell lines with higher levels of SRC expression and SRC pathway deregulation.’

That synergistic effect, in which drugs used in combination strengthen each other’s efficacy, was absent when low SRC expression and low SRC pathway deregulation were present, Teoh said.

‘These findings indicate that we may be able to direct the use of a targeted therapy like dasatinib based on gene expression pathways in select ovarian cancers,’ she said.

The results of the study are being presented on a poster at the 100th annual American Association for Cancer Research meeting in Denver on April 19, 2009. The study was funded by the Prudent Fund and the National Institutes of Health.

‘Our ultimate goal is to offer personalized therapy for women with ovarian cancer,’ said Angeles Secord, MD, a gynecologic oncologist at Duke and senior investigator on this study.

‘Hopefully in the future we will apply targeted therapies to individual patients and their cancers in order to augment response to treatment while minimizing toxic side effects.’

For this study, researchers examined four ovarian cancer cell lines, known as IGROV1, SKOV3, OVCAR3 and A2780. Three of the cell lines demonstrated high activation of SRC and one demonstrated lower SRC expression.

All were treated in lab dishes with various combinations of the chemotherapeutic agents dasatinib, carboplatin and paclitaxel.

‘We found that the addition of dasatinib to standard therapy in the three cell lines with significant SRC pathway deregulation – IGROV1, OVCAR3 and A2780 – enhanced the response of the cancer cells to therapy,’ Teoh said.

‘Conversely, in SKOV3, which has minimal SRC protein expression and pathway deregulation, we saw the least amount of anti-cancer activity when we added dasatinib.’

It’s possible that by blocking the SRC activity with the dasatinib, we are enhancing the effect of the other chemotherapeutic agents, Teoh said.

The results of this study support the further investigation of targeted biologic therapy using a SRC inhibitor in some ovarian cancers, she said. Currently a phase I trial of a combination of dasatinib, paclitaxel and carboplatin is available for women with advanced or recurrent ovarian, tubal and peritoneal cancers.

Dasatinib is a chemotherapeutic that is currently FDA-approved for use in leukemia. It is manufactured by Bristol-Myers Squibb and is sold under the brand name Sprycel. Bristol-Myers Squibb provided the dasatinib used in this study.

Other researchers involved in this study include Tina Ayeni, Jennifer Rubatt, Regina Whitaker, Holly Dressman and Andrew Berchuck.”

Source: Addition of Dasatinib to Standard Chemo Cocktail May Enhance Effect in Certain Ovarian Cancer, by Duke Medicine News and Communications, News, Health Library, DukeHealth.org, April 13, 2009.

Secondary Sources:

Tumor-Promoting Protein COX-2 Is The Target Of First Joint Symposium Between AACR & ASCO

An inflammatory protein implicated in a variety of cancers is the target of the first joint symposium between the nation’s two premier cancer research organizations.  The presidents of the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) organized the session focused on the COX-2 enzyme and cancer treatment Monday afternoon — April 20, 2:30-4:30 p.m., in rooms 205-207 of the Colorado Convention Center — at the AACR’s 100th Annual Meeting 2009 in Denver.  A similar symposium on new molecular targets will be conducted at ASCO’s annual meeting in May 29- June 2 in Orlando.  COX-2 is best known as a target for preventing dangerous polyps that lead to colorectal cancer, but it is also advancing as a target for treatment of many solid tumors. …

“Leading cancer organizations team up on tumor-promoting protein – AACR and ASCO begin joint symposia at annual meetings with focus on COX-2

An inflammatory protein implicated in a variety of cancers is the target of the first joint symposium between the nation’s two premier cancer research organizations.

duboismdander

Raymond DuBois, M.D., Ph.D., President, AACR; Provost and Executive Vice President, The University of Texas M. D. Anderson Cancer Center

The presidents of the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) organized the session focused on the COX-2 enzyme and cancer treatment Monday afternoon — April 20, 2:30-4:30 p.m., in rooms 205-207 of the Colorado Convention Center — at the AACR’s 100th Annual Meeting 2009 in Denver. A similar symposium on new molecular targets will be conducted at ASCO’s annual meeting in May 29- June 2 in Orlando.

COX-2 is best known as a target for preventing dangerous polyps that lead to colorectal cancer, but it is also advancing as a target for treatment of many solid tumors.

‘Our symposium is timely because we are starting to see data from Phase II and Phase III clinical trials about COX-2 inhibition following post-surgical chemotherapy in colon cancer patients,’ said Raymond DuBois, M.D., Ph.D., president of AACR and provost and executive vice president at The University of Texas M. D. Anderson Cancer Center.

‘There’s been a great deal of preclinical and translational research addressing COX-2 overexpression in tumors and its role in cancer growth and survival. In prevention, inhibiting this enzyme reduces the number of high-risk precancerous polyps by 66 percent,’ DuBois said. ‘The time is ripe to combine basic science and clinical expertise to advance the therapeutic potential of this approach.’

Joint efforts are critical to the development of new approaches against cancer, said ASCO President Richard L. Schilsky, M.D., professor of medicine at the University of Chicago Medical Center.

‘The development of targeted therapies for cancer prevention and treatment requires the close collaboration and combined resources of basic scientists and clinical investigators,’ Schilsky said. ‘The success of targeted therapy for cancer depends first and foremost on a comprehensive understanding of the biology of the drug target coupled with a robust assay to assess target inhibition and a drug that hits the target. With these ingredients in place, clinical trials can be designed to assess the impact of treatment in the population most likely to benefit.’

schilsky

Richard L. Schilsky, M.D., President, ASCO; Associate Dean for Clinical Research, Professor of Medicine at the University of Chicago Medical Center.

‘The AACR/ASCO Symposium illustrates these core principles and demonstrates that continued progress against cancer requires the partnership of all investigators and practitioners represented by these two great organizations,’ Schilsky said.

The idea for joint symposia at each organization’s annual meeting has been discussed for years and was advanced by immediate past presidents William Hait, M.D., Ph.D., of AACR and Nancy Davidson, M.D., of ASCO.

DuBois and Schilsky co-chair the symposium. Scheduled presentations are:

  • COX-2 and Cancer Biology by DuBois, who discovered the enzyme’s overexpression in tumors.
  • Overview of COX-2 as a Target for Cancer Treatment, by Schilsky.

*          *          *

AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. ASCO is the world’s leading professional organization representing physicians who care for people with cancer. Many scientists and physicians are members of both organizations.”

Source: Leading Cancer Organizations Team Up on Tumor-Promoting Protein – AACR and ASCO begin joint symposia at annual meetings with focus on COX-2, M.D. Anderson News Release, The University of Texas M.D. Anderson Cancer Center, April 17, 2009.

Comment:  The relationship between ovarian cancer and COX-2 remains unclear.  Some in vitro and in vivo studies make a connection between ovarian cancer and COX-2, while others suggest that COX-1 is more relevant to current ovarian cancer research.  It is an area that warrants further investigation.

Recent Studies Re Ovarian Cancer and COX-2: