DNA Repair Therapies for Ovarian Cancer Dream Team - Stand Up To Cancer

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SU2C–Ovarian Cancer Research Alliance–National Ovarian Cancer Coalition Ovarian Cancer Dream Team: DNA Repair Therapies for Ovarian Cancer

Grant Term: July 2015–June 2019

The SU2C-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team focused on developing new therapies that target DNA repair and applying them to a much larger group of women, beyond those with BRCA1 and BRCA2 mutations. By screening for inherited mutations in genes linked to DNA repair, the team worked to identify women at high risk for ovarian cancer for whom preventative measures may be lifesaving. With a combined focus on treatment and prevention, the program delivered near-term ovarian cancer patient benefit.

ABOUT THIS TEAM’S RESEARCH

Ovarian cancer is usually diagnosed at an advanced stage, when it is hard to treat, and death rates are high. Cancers with certain types of DNA repair defects are responsive to targeted therapies, such as drugs called PARP inhibitors.
The Dream Team brought together internationally renowned experts to focus on developing new therapies that target DNA repair and on expanding the use of drugs called PARP inhibitor to a much larger group of women. In addition, by screening for inherited mutations in genes linked to DNA repair, the team worked to find ways to identify women at higher risk for ovarian cancer. The team took a three-pronged approach to its goals:
1. Identify ovarian cancers that are likely to respond to DNA repair therapies.
2. Evaluate, in three clinical trials, new drug combinations that may sensitize ovarian tumors to PARP inhibitors.
3. Develop web-based genetic testing and counseling strategies and test surgical prevention models.

MEET THE TEAM

The top scientists and researchers on the SU2C–OCRA–NOCC Ovarian Cancer Dream Team come from a variety of backgrounds and disciplines, which leads them to great insights upon collaboration. Learn more about the SU2C–OCRFA–NOCC Ovarian Cancer Dream Team.

Dream Team Members

Alan D. D’Andrea, MD
Dana-Farber Cancer Institute
Leader

Elizabeth M. Swisher, MD
University of Washington
Co-Leader

Gini F. Fleming, MD
The University of Chicago
Principal Investigator

Maria Jasin, PhD
Memorial Sloan Kettering Cancer Center
Principal Investigator

Scott H. Kaufmann, MD, PhD
Mayo Clinic, Rochester
Principal Investigator

Karen H. Lu, MD
MD Anderson Cancer Center
Principal Investigator

Jamie Crase
University of Washington
Advocate

Kathleen Gavin
Minnesota Ovarian Cancer Alliance
Advocate

Deborah Polinsky
SHARE Cancer Support
Advocate

Alexandra Feinstein
Dana-Farber Cancer institute
Project Manager

Donald Watson
Dana-Farber Cancer Institute
Project Manager

“We now see defective DNA repair as a more general vulnerability of ovarian cancer. We hope to extend the use of PARP inhibitors to many other patients and find combinations with other drugs that will be effective against ovarian cancer.”

Alan D. D’Andrea, MD
Dana-Farber Cancer Institute

TEAM PROGRESS UPDATES

Stand Up To Cancer’s research projects are designed to foster collaborative, swift translational research. The hallmarks of these efforts include rigorous application and selection procedures, sufficient funding to allow scientists to focus on the objectives of the grant, and reviews by senior scientists every six months. These reviews help the investigators capitalize on the latest findings, address potential roadblocks, and collaboratively evolve as the science requires. Please click on the link to see summaries of research results so far for the SU2C–OCRA–NOCC Ovarian Cancer Dream Team.

TEAM PROGRESS UPDATES

PUBLICATIONS

A Phase I Clinical Trial of the Poly(ADP-ribose) Polymerase Inhibitor Veliparib and Weekly Topotecan in Patients with Solid Tumors
Wahner Hendrickson AE, Swisher EM, Kaufmann SH, et al. (2018)
Clinical Cancer Research 24(4):744–52.
EZH2 Promotes Degradation of Stalled Replication Forks by Recruiting MUS81 Through Histone H3 Trimethylation
Rondinelli B, Gogola E, D’Andrea AD, et al. (2017)
Nature Cell Biology 19(11):1371-1378.
USP1 is Required for Replication Fork Protection in BRCA1-Deficient Tumors
Lim KS, Li H, Roberts EA, et al (2018)
Mol Cell. 72(6):925-941.e4.
Prediction of DNA Repair Inhibitor Response in Short Term Patient-derived Ovarian Cancer Organoids
Hill SJ, Decker B, Roberts EA, et al (2018)
Cancer Discov. 8(11):1404-1421.
MAGENTA (Making Genetic testing accessible): a prospective randomized controlled trial comparing online genetic education and telephone genetic counseling for hereditary cancer genetic testing.
Rayes N, Bowen DJ, Coffin T, Nebgen D, Peterson C, Munsell MF, Gavin K, Lechner R, Crase J, Polinsky D, Romero I, Blank SV, Levine DA, Norquist BM, Swisher EM, Lu KH.
BMC Cancer. 2019 Jul 2;19(1):648.
Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial.
Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI, Mayer EL, O'Cearbhaill RE, Coleman RL, Kochupurakkal B, Whalen C, Curtis J, Farooq S, Luo W, Eismann J, Buss MK, Aghajanian C, Mills GB, Palakurthi S, Kirschmeier P, Liu J, Cantley LC, Kaufmann SH, Swisher EM, D'Andrea AD, Winer E, Wulf GM, Matulonis UA.
Lancet Oncol. 2019 Apr:20(4)):570-580
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial
Coleman RL, Oza AM, Swisher EM, et al. (2017)
Lancet. 390(10106): 1949-1961. doi: https://doi.org/10.1016/S0140-6736(17)32440-6
Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.
Färkkilä A, Gulhan DC, Casado J, Jacobson CA, Nguyen H, Kochupurakkal B, Maliga Z, Yapp C, Chen YA, Schapiro D, Zhou Y, Graham JR, Dezube BJ, Munster P, Santagata S, Garcia E, Rodig S, Lako A, Chowdhury D, Shapiro GI, Matulonis UA, Park PJ, Hautaniemi S, Sorger PK, Swisher EM, D'Andrea AD, Konstantinopoulos PA.
Nat Commun. 2020 Mar 19;11(1):1459. doi: 10.1038/s41467-020-15315-8. PMID: 32193378 Free PMC article. Clinical Trial
Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids.
Hill SJ, Decker B, Roberts EA, Horowitz NS, Muto MG, Worley MJ Jr, Feltmate CM, Nucci MR, Swisher EM, Nguyen H, Yang C, Morizane R, Kochupurakkal BS, Do KT, Konstantinopoulos PA, Liu JF, Bonventre JV, Matulonis UA, Shapiro GI, Berkowitz RS, Crum CP, D'Andrea AD
Cancer Discov. 2018 Nov;8(11):1404-1421. doi: 10.1158/2159-8290.CD-18-0474. Epub 2018 Sep 13. PMID: 30213835 Free PMC article.
The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition.
Parmar K, Kochupurakkal, Lazaro J-B, Wang ZC, Palakurthi S, Kirschmeier PT, Yang C, Sambel LA, Farkkila A, Reznichenko E, Reavis HD, Dunn CE, Zou L, Do KT, Konstantinopoulos PA, Matulonis UA, Liu JF, D’Andrea AD, Shapiro GI.
Clin Cancer Res, 2019 Oct 15;25(20):6127-6140. PMID: 31409614.
Single-Arm Phases 1 and 2 Trial of Niraparib in Combination with Pembrolizumab in Patients with Recurrent Platinum-Resistant Ovarian Carcinoma.
Konstantinopoulos PA, Waggoner S, Vidal GA, Mita M, Moroney JW, Holloway R, Le LV, Sachdev JC, Chapman-Davis E, Colon-Otero G, Penson RT, Matulonis UA, Kim YB, Moore KN, Swisher EM, Farkkila A, D’Andrea AD, Stringer-Reasor E, Wang J, Buerstatte N, Arora S, Graham JR, Bobilev D, Dezube BJ, Munster P.
JAMA Oncol, 2019 Aug 1;5(8):1141-1149. PMID: 31194228.
See MoreLess Publications

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