Funded Research:
International Collaborative Grant on Carcinosarcoma (Malignant Mixed Müllerian Tumors)
June 15, 2011: The Liddy Shriver Sarcoma Initiative is pleased to announce the funding of a $50,000 research grant, "Somatic Mutation Profiling of PI3K Pathway in Uterine Carcinosarcoma/ Malignant Mixed Mullerian Tumors." This collaborative study is being conducted by researchers in Canada and the United States. The co-principal investigators are Blaise Clarke, MD, University of Toronto, Blake Gilks, MD, University of British Columbia, Katherine Hale, PhD, MD Anderson Cancer Center, and Paul Boutros, PhD, Ontario Institute for Cancer Research.
This grant is made possible by a very generous donation made by Laura Somerville, by donations made in memory of Adrianne Pfeiffer (through several MMMT awareness events organized by her husband, Robert Pfeiffer), and by donations made in memory of Mary Anne Voeglie.
In their grant application, the four investigators noted that:
“Uterine carcinosarcoma (Malignant Mixed Müllerian Tumor) is an uncommon and aggressive neoplasm that has an extremely poor prognosis. The 5-year survival is about 35%. Therapeutic options are limited and no specific targeted therapy is available. Molecular evidence suggests that most uterine carcinosarcomas are monoclonal. Accordingly, supported by molecular, epidemiologic, genetic, and histologic data, uterine carcinosarcomas are now regarded as high-grade carcinomas with sarcomatous/stromal differentiation, similar to other organ systems. This is reflected in the use of platinum based treatment regimens similar to those used for uterine carcinomas. There is no standard second-line therapy, and identification of new and potentially 'druggable' targets is urgently needed."
They hypothesize that:
"Carcinosarcomas are high grade carcinomas with a metaplastic phenotype and have similar genomic profiles to high-grade endometrial carcinomas, specifically, abnormalities in the PI3K-AKT pathway. PTEN is a tumor suppressor gene and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated PI3K/Akt/mTor signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation and cell cycle progression.”
The investigators further observe that:
"There is clinical and pre-clinical data, including from members of our group, demonstrating the efficacy of MTOR/PI3K inhibitors in the treatment of endometrial carcinomas. A recent clinical trial conducted by the National Cancer Institute of Canada (NCIC) investigating the MTOR inhibitor Temsirolimus, showed promising single agent activity in women with advanced and metastatic endometrial cancer. Targeting the PI3K/MTOR pathway alone and in combination in endometrial cancer is being actively developed as a treatment strategy in this disease. Deforolimus, like temsirolimus, is an intravenous mTor inhibitor. In a phase II trial of women with endometrial cancer and uterine carcinosarcoma, 28% of patients had either a complete or partial response.
"Similarly, PTEN deficiency in endometrial cancer cell lines has been shown to predict sensitivity to PARP inhibitors since PTEN is thought to be involved in homologous recombination of DNA repair pathway through transcriptional regulation of RAD51. If genomic alterations in the PI3K pathway, including PTEN deficiency, are demonstrated in carcinosarcomas, targeted agents such as PI3K inhibitors and PARP inhibitors may be used in the treatment of uterine carcinosarcoma.
"In this proposal we will characterize the somatic mutation profile of members of the PI3K pathway, p53 and genes involved in DNA repair, BRCA1 and BRCA2 in an annotated cohort of uterine MMMTs. We will use Sequenom technology for those members of the PI3K pathway for whom specific hot spot mutations are known and oligonucleotide microarray gene chips to sequence those genes for which specific hot spots have not been identified (PTEN, p53, BRCA1 and BRCA2). We will also characterise protein expression of downstream mTor targets, such as phospho-PKB/Akt, phospho-p70S6K, phospho-4E-BP1 and phospho-S6 which would indicate activation of PI3K pathway activation. Other immunohistochemical (IHC) markers will include the EGFR family and PTEN, k-Ras, β-catenin and the mismatch repair genes (MLH1, PMS2, MSH2 and MSH6) in an annotated cohort of uterine carcinosarcomas. We will compare the results to ongoing work being performed by team members on a cohort of clinical trial samples in which patients with endometrial cancer were treated with mTor inhibitors. In the MMMT cohort, for cases in which no driver mutation is identified or which on immunohistochemistry is shown to have an intact PI3K pathway, we will perform copy number and somatic mutation analysis using MIP-CHIPs."
Prof Clarke stated, “By combining somatic mutation profiling with immunohistochemical analysis of protein expression we will aim to develop a comprehensive profile of this pathway, its more peripheral collaborators and molecules implicated in DNA repair, in the setting of uterine carcinosarcoma. This will facilitate future clinical trials of targeted therapeutics in this subset of cancers.”
Read more about this study in the article, "Somatic Mutation Profiling of PI3K Pathway in Uterine Malignant Mixed Mullerian Tumors," which appears in the June 2011 issue of ESUN.