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PI3K Dream Team Progress Update

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PI3K Dream Team Progress Update

Targeting the PI3K Pathway in Women’s Cancers

Funding: $15 million

Leader: Lewis C. Cantley, Ph.D., Cancer Center at Beth Israel Deaconess Medical Center
Co-Leader: Gordon B. Mills, M.D., Ph.D., University of Texas MD Anderson Cancer Center


Fast Facts on Women’s Cancers:

  • It is expected that more than 22,000 women will be diagnosed with ovarian cancer in 2013 and more than 14,000 will die of the disease.
  • In 2013, more than 49,000 new cases of endometrial cancer are projected to be diagnosed and more than 8,000 deaths are anticipated to be attributable to the disease.
  • When endometrial cancer is diagnosed early, the estimated one year survival rate is 92 percent.

 

Project Background

The phosphatidylinositol 3 kinase (PI3K) pathway is a complex signaling cascade that, in concert with other signaling networks, regulates essential cell functions such as growth, division, migration and survival. Aberrant activation of the PI3K pathway is associated with numerous cancers. These include breast, ovarian and endometrial, three “women’s cancers”, that are the focus of this project.

The scientists on this Dream Team discovered the PI3K pathway and studied its implication in human cancers. They also led the efforts in the development of drugs that can inhibit the PI3K pathway. Unfortunately, while many of these drugs are now in clinical trials, it is currently not possible to predict which tumors will respond to a PI3K inhibitor. As a consequence, many women may be given treatments that have no benefit to them, or could even cause unnecessary complications.

The goal of this Dream Team is to discover approaches that will predict which women’s cancers will respond positively to a drug that inhibits the PI3K pathway. If successful, this work will accelerate personalized cancer care that can be incorporated into standard practice.

To inquire about this Dream Team’s clinical trials, e-mail .(JavaScript must be enabled to view this email address).  If you are interested in participating in a clinical trial, please consult with your doctor. 

 

Status Update

6 month milestones
In the first 6 months of the project, this Dream Team established a website (http://www.pi3k.org) to share information with their Team and the public.  A mouse model for PI3K specific breast cancer was developed and the Team started examining characteristics of drug resistance in the tumor.  A mouse model of BRCA1 breast cancer also showed promising responses to PI3K inhibitor treatment and provided data to develop co-clinical trials later in the project. 

The Team took a personalized medicine approach in their proposal.  Biomarker assays to identify five common PI3K mutations were successfully developed and the Team started using these assays to match patients with PI3K mutations to potential treatments.  Ten phase II trials, spanning breast, ovarian, and endometrial cancers, were designed and two started enrolling during this period.

Testing of PI3K inhibitors in combination with other standard treatments was started in over 100 breast, ovarian, and endometrial cell lines.  The Team started testing promising combinations in mouse models.  The Team also successfully implanted patients’ tumor cells into mouse models.  This technique allows several treatments to be tested against a tumor before treatment is given to a patient. 

12 month milestones
During this period, the Team continued characterizing the breast, ovarian, and endometrial cancer cell lines.  Additionally, they analyzed the following patient tumor samples to determine the specific mutation (or mutations) present in PI3K:  1000 breast, 500 ovarian, and 400 endometrial cancers.

Cell-based screens for combination therapies were developed.  Drug combinations were tested in 3 dimensional cell cultures, mouse models, and patient-derived xenografts in mice.  The Team also developed new models of PI3K specific breast cancer to study mechanisms of drug resistance. 

In the first twelve months of the project, a total of 13 clinical trials to identify biomarkers and test responses to PI3K inhibitors were enrolling or set to begin: two phase I combination trials for patients with endometrial or advanced breast cancers, two phase I/II combination trials for breast cancer, and nine phase II trials testing single agent and combination therapy in endometrial, ovarian, and breast cancer. 

18 month milestones
During this period, the Team continued their biomarker studies and made some important observations.  They found that a PI3K inhibitor combined with a PARP inhibitor was effective in several breast cancer tumors, including those with a BRCA1 mutation.  Other studies showed that MYC and MET proteins may contribute to resistance to PI3K inhibitor treatment in mice that have a mutation in the PIK3CA gene.  The Team also identified three ways to measure tumor response to treatment in vitro. 

Additional cell lines were collected to continue testing combination drug therapies and 9 out of 14 planned clinical trials opened for patient enrollment during this period. 

24 month milestones
The Team continued to meet their milestones.  During this period, the Team completed additional drug combination testing in cell lines.  They also made progress in their clinical trials; approximately 500 patients were enrolled by the 24-month mark. 

The Dream Team developed several innovative screening approaches to find drug combinations that inhibit the PI3K pathway, and identify the patients whose types of tumors will respond to these drugs.  Using techniques developed during the first 18 months of the project, the biomarker working group within the Team analyzed samples collected from patients participating in clinical trials. 

30 month milestones
All of the year 1 and 2 milestones have been completed.  Ongoing trials continue to enroll and three additional drug combination trials will begin enrollment within the next few months.  One last clinical trial, a phase II study testing a broad-range PI3K inhibitor called BKM120 in patients with metastatic triple negative breast cancer was planned and, pending IRB approval, will soon begin enrollment.

The Team continues to conduct retrospective analysis on patient tissues.  In a BRCA mutant breast cancer mouse model, the Team has seen promising results using a PI3K inhibitor and PARP inhibitor in combination; tumors disappear and have not reappeared by 5 months after withdrawing the drugs.

Over twenty PI3K pathway-targeted drugs and seven drugs targeting interacting pathways have been tested in 57 breast cancer cells lines, 54 ovarian cancer cell lines, and 37 endometrial cancer cell lines to identify potentially novel biomarkers. 

36 month milestones
At the three-year mark, a total of 762 patients have been enrolled in all types of SU2C studies. A Major challenge in the implementation of the “Demonstration Trials”, which are the highest priority for the

Dream Team, has been the excessive toxicity observed when combining PI3K pathway drugs to other drugs. Most of the Dream Team’s efforts in the first 30 months was devoted to developing dosing schedules that circumvented these toxicities without reducing efficacy.

At the end of this period, the Dream Team reports the completion of all the Phase I work for two of the demonstration trials. All exploratory trials are now closed; these studies have allowed the Team to develop biomarkers for their Demonstration Trials. These exploratory trials have also been instrumental in assessing toxicities of PI3K pathway inhibitors in patients.

The Team continues to conduct retrospective analysis on patient tissues. In a BRCA mutant breast cancer mouse model, the Team has seen promising results using a PI3K inhibitor and PARP inhibitor in combination; tumors disappear and have not reappeared by 5 months after withdrawing the drugs.

Over twenty PI3K pathway-targeted drugs and seven drugs targeting interacting pathways have been tested in 57 breast cancer cells lines, 54 ovarian cancer cell lines, and 37 endometrial cancer cell lines to identify potentially novel biomarkers.

42 month milestones
All of the year one, year two, and year three milestones have been completed. The Dream Team has completed all of their “Exploratory Trials” and some of their “Discovery Trials”, and expects that all these will be completed at the end of this fourth and last year of funding. One of the three “Demonstration Trials” is open and continues to accrue well. The other two Demonstration Trials should open in the next several months; one by the end of summer 2013, and the other in the second quarter of 2014. A total of 854 patients have now been enrolled in all types of SU2C clinical studies.

In addition, the Dream Team continued to conduct retrospective analyses of patient tissues in order to identify biomarkers of response to therapy. To date, they have obtained 8398 samples from 226 patients. In parallel, the Dream Team is using cell lines and mouse models to study the same drug combinations used in their clinical trials in order to identify response biomarkers as well as biomarkers of innate and acquired resistance.

48 month milestones
The Dream Team has continued to enroll patients in the “Discovery Trials” that are still open. One study was closed due to insufficient evidence if clinical benefit, while four other Discovery Trials remain active. Two of the three “Demonstration Trials” are open and continues to accrue well. The last Demonstration Trials should open in the second quarter of 2014.

The Dream Team has also continued to conduct retrospective analyses of patient tissues in order to identify biomarkers of response to therapy. In addition, the Dream Team is using a recently validated CLIA-compliant assay to prospectively test the genetic composition of the tumors of all patients enrolled in their trials.


Fast Facts on Prevention Tips:

  • As prevention for endometrial cancer, watch for signs and symptoms, such as unusual spotting or bleeding not related to menstrual periods. Report unusual symptoms to your doctor.
  • Obesity increases the risk of both ovarian and endometrial cancer.
  • Ovarian cancer is more likely to occur in older women. Women who have never had children, who have unexplained infertility, or who have a family history of ovarian cancer are at increased risk for the disease. Please discuss your risk with your doctor.

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