The SU2C-PCF Prostate Dream Team Progress Update
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The SU2C-PCF Prostate Dream Team Progress Update
Precision Therapy of Advanced Prostate Cancer
Funding: $10 million
Leader: Arul M. Chinnaiyan, M.D., Ph.D., University of Michigan
Co-Leader: Charles L. Sawyers, M.D., Memorial Sloan-Kettering Cancer Center
Fast Facts on Prostate Cancer:
- In the United States, prostate cancer is the most common non-skin cancer and second leading cause of cancer death, in men. 1 in 7 men will be diagnosed with prostate cancer during his lifetime.
- More than 2.9 million American men are currently living with prostate cancer.
- One avenue for treatment of patients diagnosed with prostate cancer is the reduction of androgen hormones, such as testosterone and dihydrotestosterone, by chemical or surgical means. However, as with most hormone dependent tumors, prostate cancer becomes resistant to hormone-deprivation therapy. This type of cancer is referred to as “castration-resistant prostate cancer” (CRPC).
Fast Facts on Prevention Tips:
- The American Cancer Society recommends that men make an informed decision with their doctor about whether to be tested for prostate cancer. Starting at age 50, men should talk to a doctor about the pros and cons of testing so they can decide if it is the right choice for them.
- A man with a first degree relative who has had prostate cancer has an increased risk of developing the disease. Consult with your healthcare provider to assess your risk and decide on appropriate steps to take.
- Prostate cancer occurs more often in African-American men than in white men.
The Prostate Cancer Dream Team’s Research Project
Prostate cancer, like other types of cancer, is not one disease. The genetic makeup of each individual’s cancer can be different and those differences may explain why drugs that work for some patients seem ineffective for others. More and more, researchers and physicians realize that treatment decisions will require a personalized or precision approach whereby the type of treatment is chosen based on the specific genetic characteristics of individual patient’s tumors.
This Dream Team is harnessing the power of so-called next-generation sequencing technology to decode the cancer genomes of 500 patient with castration-resistant prostate cancer (CRPC), the 3.1 billion bases of DNA sequence that constitute the entire set of genetic instructions found in a human cell. This state-of-the-art technology allows researchers to sequence entire genomes relatively inexpensively, yet with speed and accuracy never achieved before.
Armed with the information about the genetic makeup of these 500 patients, the Dream Team expects to be able to direct patients toward the treatment most likely to have an effect on their specific tumor. The hope is that this personalized or precision approach will lead to more effective and lasting treatments, and potentially spare patients from unnecessary therapies that are expensive, highly toxic, and all too often provide little or no benefit.
The Dream Team is made up of an all-star cast of world-class physicians, biologists, geneticists, and bioinformatics specialists. This Dream Team is focused on patients with metastatic CRPC treated with abiraterone (Zytiga), as well as participants from other clinical trials that used novel therapies to treat metastatic CRPC. This Dream Team will systematically evaluate patients to identify ways that they can predict those patients whose cancer responds to the therapies, but also those patients whose cancers resist the therapies.
For patients with cancers that do not respond to a given therapy, the Team will assess if individual genetic changes might suggest potential other therapeutic approaches. In parallel, the Team will also perform laboratory studies of CRPC treatments to test the predictors of response and/or resistance. These laboratory studies will help the Dream Team to identify and prioritize the best drug targets.Status Update
During the first 6 months, the Dream Team has laid the foundation for executing their proposed studies.
- All 5 clinical sites have secured regulatory approval and are now enrolling patients;
- A unified and efficient pipeline for collecting and processing patient tumor samples has been established;
- Sequencing of patients’ tumors is underway. On the basis of certain mutations identified in their tumors, seven patients have been directed to participate in a specific Phase II clinical trial, one comparing treatment with abiraterone together with the investigational drug ABT888 (also known as veliparib) or abiraterone alone; and
- The Dream Team also is conducting preclinical studies in mice to elucidate the mechanisms of resistance to treatment with either abiraterone or enzalutamide (Xtandi). The clinical importance of the mechanisms identified will be examined in patients enrolled in the clinical trials.
By the end of year 1, the Dream Team expects to have a) enrolled and biopsied 100 patients in the CRPC study, b) carried out sequence analysis of all successful biopsies, c) established a web portal for data sharing and viewing, and d) completed one pre‐clinical xenograft study.
During the first year, the Dream Team has laid the foundation for executing their proposed studies.
- All 5 clinical sites are actively enrolling patients and collecting and processing patient tumor samples.
- Preliminary data from sequencing patients’ tumors suggests that there may be common genetic changes in castration resistant prostate cancer.
- Clinical data supports that PARP inhibitors may be beneficial to treat CRPC patients with BRCA mutations.
- Olaparib works well against sporadic advanced prostate cancer and efforts are ongoing to define the tumor characteristics of responding patients.
- Response to ABT-888/Abiraterone has been observed and further analyses will determine if response is related to specific genetic changes (TMPRSS2/ERG rearrangements).
In the next 6 months, the Dream Team expects to a) continue sequencing and upload onto a portal so that all team members have access, b) continue clinical trial recruitment and tumor collection, c) complete the second phase of the animal studies assessing chemotherapeutic agents (MDV3100, PARP inhibitors, and XL184).
During the 13-18 month period of the project, this Dream Team has made significant progress towards their goals.
- Of the 189 patients enrolled in clinical trials, 126 patient samples’ tumors have been sequenced.
- Results from these sequencing efforts revealed that two genes (called TP53 and FLT4) are frequently mutated, and confirmed the known status of Androgen Receptor gene amplifications.
- Continued development of mouse models for CRPC and testing treatment agents using these models.
- Continued improvements to the process for collecting patient’s samples.
- Discovered new changes in cellular pathways that may have immediate implications for patients who harbor specific mutations.
In the next 6 months, the Dream Team expects to continue the studies listed above. In addition, they will be starting two new clinical trials to study the development of resistance to enzalutamide.
During the 19-24 month period of the project, this Dream Team has continued to work towards providing clinically valuable information to improve the lives of patients with prostate cancer. To this extent, they have:
- Enrolled over 348 patients in clinical trials, from which 234 patients’ tumors have been successfully characterized.
- Conducted an initial analysis of the first 150 patients’ samples
- Identified a diversity of molecular alterations in advanced castration-resistant prostate cancer, a number of which are plausibly responsible for tumor progression.
- Generated the largest collection of genomic data on metastatic castration-resistant prostate cancer patients to date.
- The Dream Team is currently working on a sharing their results, which will lead to improved understanding of the molecular basis, as well as clinical management of CRPC.
In the next 6 months, they will continue to enroll patients in biopsy studies, complete the next phase of the mouse studies, continue to perform data analysis, and make improvements to their database that houses all their data.
During the 25-30 month period of the project, this Dream Team has:
- Continued patient enrollment in clinical trials and the analysis of samples.
- Conducted an initial analysis of the first 150 patients’ tumor samples. The Team has found the following:
- Several, diverse genetic changes in advanced CRPC tumor samples, some of which are plausibly responsible for tumor progression.
- 89% of patients with CRPC had tumor cell changes that may be good targets for treatment.
- This work was published in a high impact journal, Cell.
- The Team’s efforts thus far have resulted in the largest collection of genomic data on mCRPC patients to date, that will lead to improved understanding of the biological basis as well as clinical management of CRPC.
During the next 6 months, the Team will continue to enroll patients in biopsy studies and focus on obtaining repeat biopsies to follow cancer progression. Analysis of these samples will continue.
The Team has continued to make progress toward their objectives in the 30-36 month funding period. Specifically, progress has been marked by the following:
- A total of 559 patients have been enrolled on the study across all five sites and 301 patients have been successfully sequenced. This is the largest collection of genomic data on mCRPC patients to date.
- The Team recently reported that prostate cancer patients with specific mutations in genes involved in a process called DNA repair respond well to a drug called olaparib (currently FDA approved to treat ovarian cancer).
- Enrollment for the next phase this clinical trial, called TOPARP, is underway.
- The team is continuing focused efforts on patients that have failed or progressed on therapies to find out how resistance occurs and what biomarkers doctors can use to identify resistant tumors.
- The genomic data of the 150 metastatic prostate cancer samples have been released to the public via a web-based platform called cBioPortal (cbioportal.org).
- Bone metastases analyses in patients enrolled in drug studies are underway, with 70-80% of bone biopsies containing tumor cells. These tumor cells are undergoing genomic analyses.
A no-cost extension has been approved for the Dream Team to continue their work into a 4th year. During the next 6 months, the Team will continue enrolling patients in their precision medicine biopsy studies. They will emphasize analyses on repeat biopsies, in which they go back to a patient who tumors continue to grow or return despite treatment, and gather additional tumor samples. The Dream Team will use these repeated biopsies to understand how resistance occurs. The team will continue laboratory studies using animal and organoid (tumors-in-a-dish) models and expand on their techniques in evaluating metastatic bone disease in advanced prostate cancer patients.
The Team has continued to make progress toward their objectives in the 36-42 months funding period. Specific highlights are included below.
- All clinical trials are steadily accruing patients.
- The Team has completed comparing the methods and technology applied across all the SU2C clinical trial sites that are performing gene sequencing. This confirms and validates the successful collaborative nature of the SU2C-Prostate Cancer Foundation Dream Team model.
- Preclinical studies using mouse models and tumor organoids are continuing to progress.
- A large study was published showing that approximately 10-15% of mCRPC patients carry a mutation specific to DNA repair that is an inherited genetic mutation. Not only do these mutation carriers have a worse prognosis from localized prostate cancer and develop faster resistance, but these results suggest that genetic screening may be strongly encouraged in mCRPC patients as treatment options may differ depending on whether or not they carry the DNA repair mutation(s).