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The SU2C-PCF Prostate Dream Team 2 Progress Update

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The SU2C-PCF Prostate Dream Team 2 Progress Report

Targeting Adaptive Pathways in Metastatic Treatment Resistant Prostate Cancer

Funding: $10 million

Leader: Eric J. Small, M.D., UCSF Comprehensive Cancer Center
Co-Leader: Owen N. Witte, M.D., UCLA

Fast Facts on Prostate Cancer:

  • Prostate cancer is the second most common cause of cancer death for men in the United States.
  • More than 2.9 million American men are currently living with prostate cancer.
  • Despite a number of recent treatment advances, prostate cancer can rapidly become resistant to treatment and lead to significant pain, suffering, and death.

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.
  • African American men are 56% more likely to develop prostate cancer compared with Caucasian men and nearly 2.5 times as likely to die from the disease.


Project Background

The Prostate Cancer Dream Team’s Research Project

There have been a number of recent breakthroughs in the treatment of prostate cancer that has spread to other parts of the body and is no longer responding to initial hormonal therapy, so-called metastatic treatment resistant prostate cancer (mTRPC). Unfortunately, in most cases, mTRPC eventually becomes resistant to the new drugs, often over a period of only months, resulting in significant pain, suffering, and death. The goal of this Dream Team is to improve the outcome for men with mTRPC who are no longer responding to their treatment by understanding the causes of resistance, and developing treatments to overcome them.

This Dream Team is exploring the idea the prostate cancer cells using common biological responses, called adaptive pathways, to escape the effects of anti-cancer drugs and become resistant. The team believes that by identifying these pathways and blocking them, they will be able to overcome drug resistance and profoundly improve survival and quality of life for patients.

To test their idea, the Dream Team will comprehensively analyze patient tumor biopsies and blood samples for their biological make-up and to find out what pathways are turned on and off in the cancer cells. Once they identify the pathways that are turned on in mTRPC tumors, the Dream Team will devise approaches that block the resistant pathway in addition to the original treatment (co-targeting). They will validate this co-targeting approack in laboratory studies before moving to molecularly guided clinical trials to test novel co-targeting drug combinations. By combining established therapies with new treatments that co-target adaptive pathways, the Dream Team hopes to dramatically improve outcomes for men with mTRPC.

The Dream Team also proposes to centralize and integrate the considerable amount of data it will generate into a new online platform called MedBook, which will use a simple social media concept to support information exchange and discussion. The centralized information will be updated continuously based on new data, and will contribute to categorizing the most relevant adaptive pathways in mTRPC. This information will be instrumental to the Dream Team’s Clinical Working Group, which is responsible for recruiting patients to specific trials.

Status Update:

6 Month:
During the first 6 months, this Dream Team has laid the foundation for executing their proposed studies. They have:

  • Established protocols and obtained institutional review board (IRB) approval for collection of patient samples.
  • Optimized new technologies to study and analyze the collected patient samples.
  • Identified adaptive pathways likely to be responsible for resistance.
  • Developed and obtained drugs that may target some of the adaptive pathways likely to be responsible for resistance.
  • Developed a platform to share results in real-time with all participating institutions.

By the end of year 1, the Dream Team expects to have a) initiated patient enrollment at each site; b) enrolled eligible patients from the biopsy protocol into trials co-targeting both the initial pathway and the adaptive pathways activated in mTRPC resistant to currently available therapies; c) developed and validated a molecular signature to guide trials; and d) optimized the web-based data-sharing tool.

12 Month:
During the first 12 months, this Dream Team has:

  • Opened their tumor and blood collection protocol across all 5 clinical sites.
  • Collected tumor and blood from 56 patients.
  • Started molecular analysis of the patients’ samples.
  • Transitioned to a website platform (Medbook) for data sharing
  • Continues to identified adaptive pathways likely to be responsible for resistance

During the next six months, the Dream Team expects to a) maximize tumor/blood collection at each site and enroll eligible patients from this protocol onto shared clinical trials across the Dream Team, b) expand a clinical trial due to positive results regarding pathway changes that are common to mTRPC tumors (Androgen Receptor signature) and carry out additional molecular analysis on an increased number of samples, c) continue to evaluate molecular signatures (kinase profiles, autophagy, and Androgen Receptor pathways), and d) continue to transition to a website platform (Medbook), including loading of all clinical and laboratory data.

18 Month:
During this period, this Dream Team has:

  • Collected tumor and blood samples from over 90 patients.
  • Continued molecular analysis of the patients’ samples.
  • Data generated is being put into a web-based tool called Medbook.
  • Identified important information about adaptive pathways in cells that are likely to be responsible for resistance to treatment.
  • Developing clinical trials that target adaptive pathways.

Thus far, this group’s work has led to an expanded clinical trial that uses an Androgen Receptor biomarker to better identify which patients will respond to treatment. In the next 6 months, this group will continue to collect and analyze patient samples and upload them into MedBook. They will also develop assays to analyze circulating tumor cells, which will allow analysis of disease and treatment response in blood samples. In addition, they will work on a new sub project focused on how tumor-associated mutations affect the immune system’s response.

24 Month:
During this period, this Dream Team has made the following progress:

  • Opened tumor collection protocols across all 5 clinical sites and collected 137 biopsies.
  • Conducted comprehensive molecular analysis of the biopsies and circulating tumor cells.
  • Clinical and molecular data are being integrated and housed on the MedBook analytic website, which serves as a clearing house for all of the data collected.
  • Made important discoveries the mechanisms by which tumors are able to avoid treatment.
  • Continue to focus on adaptive pathways that allow metastatic castration-resistant prostate tumors to become resistant to anti-cancer treatments, and to develop clinical trials that co-target adaptive pathways.

Over the next 6 months, the Dream Team will continue to acquire patient biopsies and analyze them. They will use their database, MedBook, to analyze and share the data, and will work on improving MedBook.

30 Month:
During this period, this Dream Team has made the following progress:

  • Have over 150 patients involved in the study, which includes over 180 distinct tumor biopsies.
  • Conducted comprehensive molecular analysis of the biopsies’ biological make-up.
  • They continue to upload clinical and molecular data to the MedBook analytic website and develop tools for analysis.
  • Identified a new aggressive subtype of prostate cancer termed Intermediate Atypical Carcinoma (AIC).
  • They continued to study how tumors are able to develop resistance to anti-cancer drugs.

Over the next 6 months, they will maximize biopsy acquisition and patient enrollment. They will use complementary analyses to develop a full genomic profile of each tumor. They will also focus on additional routes of drug resistance in the patients and assess the genomic changes that are associated with resistance to abiraterone and enzalutamide. They also hope to fully implement MedBook including a patient view page that will facilitate the development of personalized medicine approaches in mTRPC.

36 Month:
During this period, this Dream Team has made the following progress:

  • Obtained and evaluated 221 biopsies to date. Of these, 75% have provided enough tumor material to allow molecular analyses.
  • Completed several co-targeting clinical trials and opened a number of other studies.
  • Early findings have revealed different biological patterns in biopsies from patients treated with enzalutamide compared to treatment with abiraterone. These results will help to identify patients that are resistant to enzalutamide or abiraterone and to identify potential novel drug combinations that will overcome resistance.
  • Continued analysis on patients whose tumors could be classified as the new aggressive prostate tumor subtype called Intermediate Atypical Carcinoma (IAC).
  • The data indicates that this new tumor subtype carries a prognosis worse than other CRPC subtypes such as prostate adenocarcinoma.
  • Having this data, the team is prioritizing the infrastructure to deliver accurate and rapid assessment of biopsies for fast return to clinicians.
  • Continued to refine laboratory models to study resistance to abiraterone and enzalutamide.
  • Developed several new interfaces or apps and enhanced existing apps for Medbook.

A one year, no-cost extension (NCE) is in place for this team to allow them to continue their work for a 4th year. The principal goal of the NCE period is to complete analysis of 300 biopsies, with a focus on paired samples.

42 Month:
The Dream Team continues to make progress in their last year of funding. Biopsies are now being collected regularly, and tissue is being analyzed across multiple platforms. Specific highlights are described below.

  • Obtained 255 biopsies including 42 patients that have had biopsies obtained at more than onetime point. The goal is to obtain 300 biopsies by the end of 2016.
  • Three new clinical trials testing different molecular inhibitors in patients whose disease have progressed despite initial treatment with either abiraterone or enzalutamide have gained funding from other sources and are planning to open this year.
  • The characterization of the new histologic subtype, IAC, continues. IAC is an aggressive cancer with a prognosis much worse than CRPC cases that are classified as prostate adenocarcinoma.
  • The Team is continuing to validate less invasive ways of defining prostate tumor types, namely, by analyzing blood samples collected from prostate cancer patients.
  • The Team’s MedBook informatics platform has been upgraded to integrate another common informatics platform, cBioPortal.

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