2011 ASCO: Matching Targeted Therapies To Specific Tumor Gene Mutations Key to Personalized Cancer Treatment

Customizing targeted therapies to each tumor’s molecular characteristics, instead of a “one-size-fits-all” approach by tumor type, may be more effective for some types of cancer, according to research presented today at the American Society of Clinical Oncology annual meeting by the M.D. Anderson Cancer Center. In patients with end-stage disease, matched patients achieved a 27% response rate, versus 5% in those unmatched.

Customizing targeted therapies to each tumor’s molecular characteristics, instead of a “one-size-fits-all approach” by tumor type, may be more effective for some types of cancer, according to research conducted by The University of Texas M.D. Anderson Cancer Center.

Apostolia M. Tsimberidou, M.D., Ph.D., Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

M.D. Anderson’s phase I clinical study findings were presented today on the opening press program of the 47th Annual Meeting of the American Society of Clinical Oncology. Apostolia-Maria Tsimberidou, M.D., Ph.D., associate professor in the M.D. Anderson Department of Investigational Cancer Therapeutics, and the principal investigator of the study, presented the data.

Marking the largest scale on which this approach has been examined to date, the study analyzed the results of matching targeted therapies with specific gene mutations in patients. The data indicated that this strategy was associated with higher rates of response, survival and failure-free survival than observed in non-matched patients.

Pairing Patient and Treatment

“This preliminary study strongly suggests that molecular analysis is needed to use the right drug for the right patient. Up to this point, we have treated tumor types, but this study shows we cannot treat all patients with a tumor type the same way. We need to take into consideration a number of factors, and this study suggests that a personalized approach is needed to improve clinical outcomes for patients with cancer,” said Tsimberidou.

The identification of pathways involved in carcinogenesis, metastasis and drug resistance; new technologies enabling tumor molecular analysis; and the discovery of targeted therapies have stimulated research focusing on the use of targeted agents as part of a personalized medicine approach, she said.

“Over the past decades, a personalized medicine approach using Gleevec has changed the way we treat chronic myeloid leukemia, as well as survival rates,” said Razelle Kurzrock, M.D., professor and chair of the M.D. Anderson Department of Investigational Cancer Therapeutics. “We wanted to apply a similar approach to solid tumors.”

“Ultimately, to best match treatments to patients and offer the most therapeutic benefit, assessing a patient’s molecular markers has to become the standard at diagnosis. … 

This study affirms what we in the cancer community have been talking about for a decade – matching drugs to patients. The time is now. The drugs are here. The technology is here, and with our program at M.D. Anderson we can bring the two together in hopes to offer the most personalized care for our patients. …”

–Razelle Kurzrock, M.D., Professor & Chair, Department of Investigational Cancer Therapeutics, University of Texas M.D. Anderson Cancer Center

Research Methods and Results

In the initial analysis, Tsimberidou analyzed 1,144 patients with metastatic or inoperable cancer who underwent testing for molecular aberrations at M.D. Anderson. Their median age was 58, and the median number of prior treatments was four. Of these patients, 460 had one or more gene aberrations, including:

  • 10 percent with a PIK3CA mutation;
  • 18 percent with a KRAS mutation;
  • 8 percent with a NRAS mutation;
  • 17 percent with a BRAF mutation;
  • 3 percent with an EGFR mutation;
  • 2 percent with a CKIT mutation;
  • 21 percent with a PTEN loss; and
  • 37 percent with a p53 mutation

Patients with gene aberrations were treated on clinical trials with matched targeted agents, when available. Regimens included one or more therapies targeting PIK3CA, mTOR, BRAF, MEK, multikinases, KIT or EGFR. Outcomes of patients with gene aberrations treated with matched therapy were compared with those patients with gene aberrations who were not treated with matched therapy because of issues such as eligibility, study availability; insurance coverage and/or logistical problems with the study calendar.

For the 175 patients with one aberration, the response rate was 27 percent with matched targeted therapy. The response rate was 5 percent in 116 patients when treated with non-matched therapy.

Patients who received matched targeted therapy had median survival of 13.4 months, while median survival for patients treated with unmatched targeted therapy was nine months. Median failure-free survival in patients who received matched targeted therapy was 5.2 months, compared to 2.2 months for patients who received unmatched targeted therapy.

Further Research Needed

These preliminary results merit further investigation and confirmatory, prospective studies are needed, especially because the study was not a randomized study and therefore biases could influence the results.

“M.D. Anderson’s goal is to better understand the biology involved in each patient’s carcinogenesis by testing each tumor for genetic abnormalities driving tumor growth to guide treatment selection. This strategy will lead to the optimization of personalized therapy,” Tsimberidou said.

Another goal is to match targeted therapies to patients earlier in treatment.

“When Gleevec was first introduced, it was tested in patients in blast crisis and the response rate was about 15 percent. In contrast, when tested in the front line setting, and with the introduction of similar but increasingly potent second- and third-generation drugs, patients’ response rate was close to 100 percent, and now their expected survival is 25 years and counting,” said Kurzrock. “Ultimately, to best match treatments to patients and offer the most therapeutic benefit, assessing a patient’s molecular markers has to become the standard at diagnosis.”

About the Phase I Program – The Time is Now

The M.D. Anderson’s Phase I program is the largest of its kind and accounts for the majority – but not all – of the institution’s earliest clinical studies. In 2010, of the 11,000 patients who participated in M.D. Anderson clinical trials, more than 1,150 were enrolled in one of the 120 Phase I trials in the program.

Currently, tumors are tested for up to 12 molecular aberrations, but at the rate technology is rapidly advancing, Kurzrock expects that number to climb to more than 100 in the near future.

Patients treated in the Phase I Program are typically very ill and all other approved therapies have failed them. Yet they are “fighters” who are willing to try anything, including studies not specific to their diagnosis to test the effectiveness of a new drug, drug combination or delivery method, said Kurzrock.

“This study affirms what we in the cancer community have been talking about for a decade – matching drugs to patients,” said Kurzrock. “The time is now. The drugs are here. The technology is here, and with our program at M.D. Anderson we can bring the two together in hopes to offer the most personalized care for our patients.”

In addition to Tsimberidou and Kurzrock, other authors on the all-M.D. Anderson study included N. G. Iskander, David S. Hong, M.D., Jennifer J. Wheler, M.D., Siqing Fu, M.D., Ph.D., Sarina A. Piha-Paul, M.D., Aung Naing, M.D., Gerald Falchook, Filip Janku, M.D., Ph.D., all assistant professors of the Department of Investigational Cancer Therapeutics; Raja Luthra, Ph.D., professor, Department of Hematopathology, Research and Sijin Wen, Ph.D., Division of Quantitative Sciences.

Libby’s H*O*P*E*™ Commentary — Use of Molecular Profiling and Chemosensitivity Testing To Determine Individualized Ovarian Cancer Treatment

It is wonderful that various medical research institutions, including M.D. Anderson, are beginning to match targeted therapies to a patient’s specific molecular tumor characteristics. This approach is generally referred to as “molecular profiling,” and it represents one promising method of matching an individual cancer patient to an effective therapy. As noted in the related Libby’s H*O*P*E*™ postings set forth below, there are several medical and scientific institutions which are pursuing development of molecular profiling for clinical study use. In the most recent related posting listed below, we discuss the molecular profile testing that is commercially available through The Clearity Foundation and Caris Life Sciences.

In the future, it may be helpful to use a form of chemosensitivity testing (e.g., the type of testing provided by Precision Therapeutics, Rational Therapeutics, and the Weisenthal Cancer Group), which is based upon the measurement of actual cancer cell death, as a second method to match a cancer patient to a potential drug or drug combination within the context of a clinical study. In fact, we would like to see a future prospective, randomized ovarian cancer clinical trial in which enrolled women are provided with treatment after assignment to one of three clinical trial arms:  (i) treatment based upon the standard of care (e.g., paclitaxel and carboplatin), (ii) treatment based upon molecular profiling, or (iii) treatment based upon chemosensitivity testing.  This type of study may uncover additional ovarian cancer treatment insights (both molecular and functional) with respect to the most lethal gynecologic cancer, while ultimately helping women with forms of the disease that may not possess a known molecular characteristic that is potentially “targetable” by an existing clinical trial drug or compound.

This combination of “bottom-up” scientific research (i.e., molecular profiling) performed side-by-side with “top-down” research (i.e., chemosensitivity testing) may represent an effective and efficient approach — albeit provocative — for evaluation of optimal personalized ovarian cancer treatment.

It is important to note that Libby’s H*O*P*E*™ and its founder Paul Cacciatore do not receive financial renumeration or benefit of any kind from the companies referred to in the paragraphs above.

About the University of Texas M.D. Anderson Cancer Center

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. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For seven of the past nine years, including 2010, 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.

Primary Sources:

Secondary Sources:
Related Libby’s H*O*P*E* Postings:

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.