The SU2C-MRA Melanoma Dream Team Progress Update
PI3K Dream Team | Pancreatic Dream Team | CTC-Chip Dream Team | Epigenetic Dream Team 2009 | Breast Cancer Dream Team | Prostate Cancer Dream Team 1 | Prostate Cancer Dream Team 2 | Melanoma Dream Team | Immunology Dream Team | Sta Op Tegen Kanker Translational Research Team | Pediatric Cancer Dream Team | Pancreatic Cancer Dream Team 2 | Tumor Organoids Dream Team | HPV Translational Research Team | Epigenetic Dream Team 2014 | Lung Cancer Dream Team | Colorectal Cancer Dream Team | Ovarian Cancer Dream Team
The SU2C-MRA Melanoma Dream Team Progress Update
Personalized Medicine for Patients with BRAF Wild-Type (BRAFwt) Cancer
Funding: $6 million
Leader: Jeffrey M. Trent, Ph.D., F.A.C.M.G., Translational Genomics Research Institute
Co-Leader: Patricia M. LoRusso, D.O., Barbara Ann Karmanos Cancer Institute (Current Institution: Yale Cancer Cancer)
Fast Facts on Melanoma:
- Melanoma is the deadliest of all skin cancers. It accounts for less than 2 percent of skin cancers, but more than 70 percent of skin cancer-related deaths.
- Melanoma of the skin is the 5th most common cancer diagnosed in the U.S.
- Early diagnosis is key to melanoma survival. More than 90 percent of patients can be cured with surgery if melanoma if detected early enough. In contrast, patients with metastatic stage 4 melanoma have a median life expectancy of less than one year.
Fast Facts on Prevention Tips:
The Melanoma Dream Team’s Research Project
Currently, patients who develop metastatic melanoma have a dismal prognosis, with a median survival of six to nine months and a five-year survival rate of 10 to 15 percent. About half of patients with metastatic melanoma have a mutation in a gene called BRAF in their tumors. For many of these patients there are approved drugs that help prolong survival. However, the other half of patients have no mutation in their tumors’ BRAF genes and are said to be BRAF wild type (BRAFwt). Very little progress has been made to identify new drugs to treat patients with BRAFwt metastatic melanoma.
This Dream Team is investigating the use of a personalized medicine approach in patients with BRAFwt metastatic melanoma in which the precise biological make-up of each patient’s tumor is used to decide the best drugs – approved or experimental - to treat that patient. Team members are profiling the biological make-up of BRAFwt and BRAF-mutant cancer cells in the laboratory and testing for sensitivity to 100 prioritized compounds that might become into new treatments. Researchers are using these data to predict the sensitivity of BRAFwt melanomas to specific drugs. They will test these predictions in laboratory studies of the melanoma cell lines and tumor tissue taken from patients. They are conducting a clinical trial that will determine whether this personalized approach significantly improves clinical outcome. The goal is a 30 percent improvement in tumor response relative to standard-of-care therapy.
The Dream Team hopes that an individualized medicine approach to the treatment of BRAFwt metastatic melanoma will not only lead to therapeutic benefit for these patients, but may also be beneficial to many other tumor and disease types.Status Update:
In the first six months, the Team has reported progress on each of the specific aims. First, they have designed, drafted, and obtained preliminary regulatory approval for the pilot clinical trial, with the first patient enrolled on November 27, 2012. Second, they have assessed different algorithms (sets of mathematical formulas) designed to identify the best treatment for a patients cancer based on that cancer genomic analysis, algorithm development strategies, and compilation of public domain data that can be used to define, evaluate, and contrast algorithms. Third, they have continued analysis of various BRAFwt melanoma cell lines to help identify ways that cancer cells respond to or become resistant to drugs that inhibit two protein targets (MEK and ERK). Finally, they have obtained agreement from pharmaceutical companies to supply 22 novel targeted drugs and initiated a formal dialog with the FDA regarding submission of Investigational New Drug (IND) and Investigational Device Exemption (IDE) regulatory applications necessary to begin the randomized clinical trial.
In the second reporting period, the Dream Team has made progress toward each of the specific aims. First, they have enrolled, biopsied, completed molecular characterization, and held Tumor Boards for three of the five patients needed for the pilot clinical trial. The final two patients for the clinical trial have consented and will go through the process soon. This has led to insights into the process and to subsequent refinement of procedures. Second, they have accumulated a pool of 27 agents to test and are negotiating with companies to obtain eight additional investigational agents. Third, they have drafted a clinical protocol for the randomized clinical trial and have scheduled an additional meeting with the FDA regarding submission of the Investigational New Drug (IND) application for the clinical trial. Finally, they have continued to assess different strategies to analyze data from the public domain that can be used to evaluate multiple algorithms to predict tumor drug sensitivity, to evaluate BRAFwt melanoma cell lines to determine drug response and resistance, and to study melanoma cell pathways that can be targeted to kill tumors.
In the third reporting period, the Dream Team has made progress as highlighted below:
- Completed enrollment and molecular profiling of all five patients enrolled on the pilot feasibility trial.
- Assessed different strategies to analyze and compile data from the public domain that can be used to define, evaluate, and contrast algorithms to predict tumor sensitivity to drugs.
- Continued evaluation of various BRAFwt cell lines to help define mechanisms of drug response/resistance.
- Continued studies of cellular programs in melanoma cells that can be targeted to kill the tumor.
- Obtained agreement from pharmaceutical companies to provide 9 novel targeted agents and continued discussions to obtain 8 additional agents.
- Wrote a final draft of the clinical protocol for the randomized trial.
- Submitted an Investigational New Drug (IND) application, which is required in order to begin the randomized clinical trial.
During the next six months, this Dream Team proposes to: (1) begin drafting two manuscripts describing experience with the pilot study, (2) conduct experiments to screen drugs in melanoma cell lines to help define mechanisms of response/resistance and target cellular pathways to promote tumor cell death, (3) gain FDA approval of the IND and IRB approval of the clinical protocol and (4) begin enrollment of patients on the randomized trial.
In the 18-24 month period, the Dream Team reports opening of the clinical trial and recruitment of the first patients. The Dream Team now has a pool of 30 drugs to use in the trial, 10 of which are new investigational drugs, with negotiations continuing to obtain an additional six agents. The Dream Team also reports continued studies of cellular programs in melanoma cells that can be targeted to kill the tumor, and development of promising new drugs that they hope to move to clinical trials.
In the 24-30 month period, the Dream Team reports:
- Rapid (average time of 4 weeks) molecular profiling and Tumor Board assessment of their first two clinical trial patients.
- Progress in development of algorithms for tumor genomic-profile drug (TGPD) matching using tumor cells grown in the laboratory.
- Sharing of data and biocomputing methods with other Dream Teams and with the scientific community at large through scientific publications.
In the 30-36 month period, the Dream Team reports:
- Reopening of the clinical trial after the lead clinical and coordination site moved to Yale University, with new patient enrollment.
- Progress in identifying subtypes of metastatic melanoma. By understanding the biology of these subtypes the Dream Team is developing new drugs that will be most effective in different subtype.
- Success in growing patients’ tumors in laboratory mice for analysis and drug testing.
In the 36-42 month period, the Dream Team reports:
- Continued enrollment of patients in the clinical trial across eight different centers, with 18 additional patients on the trial since the last report period.
- An average time of 22 days from tumor biopsy to Tumor Board Assessment for treatment recommendations.
- Continued success in growing patients’ tumors in laboratory mice for analysis and drug testing. The successful number of patient-derived tumors growing in laboratory mice is now 10 with several others in different stages of the process.
In the 42-48 month period, the Dream Team reports:
- Continued enrollment of patients in the clinical trial across eight different centers, with 9 additional patients enrolled on the trial since the last report period.
- They have modified the clinical trial to focus on one particular drug called MEK162 because this was the drug to which 20 of the initial 23 patients profiled were matched.
- They have made continued progress in their laboratory studies to predict which drugs and drug combinations are likely to be the most effective against cancer cells based on the cells’ genetic and molecular make-up.
- They have successfully grown patients’ tumors in laboratory mice (total of 19 different tumors have “taken” and grown in the mice so far). This will allow the researchers to test drugs and drug combinations against the tumors.