Paul Basilio, MDLinx | November 02, 2017
New research shows that the investigational drug talazoparib caused regression of patient-derived xenografts (PDXs) in triple-negative breast cancers with BRCA mutation. The effect was also seen in those without BRCA mutations but with other alterations in DNA damage-repair pathways. The findings were published in Clinical Cancer Research.
Patients with triple-negative breast cancer who do not respond to preoperative neoadjuvant chemotherapy have a decreased chance of long-term survival, according to study author Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics, medical director of the Institute for Personalized Cancer Therapy, and Nellie B. Connally Chair in Breast Cancer Research at The University of Texas MD Anderson Cancer Center in Houston. There is a great need for new treatment options for these patients.
“Developing animal models that are well characterized gives us an opportunity to test new agents and better understand how to best treat these patients,” Dr. Meric-Bernstam added. “Ultimately, we would like to better deliver personalized cancer therapy by understanding how we can best match therapies to patients.”
PDXs are tumor models derived directly from patient tumors and grown in mice, and as a result they may better reflect the complexity of human tumors than traditional models, she explained.
The team of researchers developed 26 PDXs using tumors from 25 patients—24 of these had triple-negative breast cancer. Twenty-two PDXs were derived from residual tumors after neoadjuvant chemotherapy. Results showed the PDX models varied significantly in their responsiveness to different standard-of-care chemotherapies, as well as to targeted therapies in development.
“The PDX models we generated varied dramatically in their genomic characteristics, potentially giving insight into why it has been challenging to truly personalize cancer therapy,” she said.
The researchers tested several investigational agents based on data obtained by sequencing the tumor exomes. The pan-PI3K inhibitor buparlisib was tested against seven PDXs, the mTOR inhibitor TAK228 against eight PDXs, the MEK1/2 inhibitor trametinib against eight PDXs, and the PARP1/2 inhibitor talazoparib against 13 PDXs.
Buparlisib, trametinib, and TAK228 had growth inhibitory effects, but they did not cause regression of any of the PDXs against which they were tested.
“Among targeted therapies, the efficacy of PARP inhibitors was most striking,” Dr. Meric-Bernstam said.
Of the PDXs treated with talazoparib, five regressed and one showed stable disease for at least 28 days. Four of these five PDXs did not harbor germline BRCA1/2 mutations, but had alterations in other DNA repair pathways, including ATM deletion and other alterations in BRCA2.
Currently, the team is developing new PDX models of triple-negative breast cancer to better determine which models are sensitive to PARP inhibitors, and to get a more comprehensive picture of the determinants of PARP inhibitor sensitivity.
They are also conducting an investigator-initiated clinical trial to test whether talazoparib is efficacious in other tumor types with DNA damage repair alterations beyond germline BRCA mutations.
Three PARP inhibitors are currently FDA-approved: olaparib and rucaparib are approved for certain women who have ovarian cancer with BRCA gene mutations, and niraparib is approved to treat both BRCA mutation-positive and BRCA mutation-negative ovarian cancers.
“Our studies show that PARP inhibitors may have efficacy in selected patients outside of germline BRCA mutation, potentially those with other alterations in DNA damage repair genes,” Dr. Meric-Bernstam said.
The study was funded by the National Institutes of Health, the MD Anderson Cancer Center Moonshot Program, the Nellie B. Connally Breast Cancer Research Endowment, a Susan G. Komen Foundation for the Cure grant, The Cancer Prevention and Research Institute of Texas, the Barr funds, and a Stand Up To Cancer (SU2C) Dream Team Translational Research Grant.
Dr. Meric-Bernstam has received commercial research grants from Novartis, AstraZeneca, eFFECTOR, Zymeworks, PUMA, Curis, Taiho, Genentech, Calithera, Debio, Bayer, Aileron, Jounce, and CytoM. She is a consultant/advisory board member for Dialecta, Darwin Health, GRAIL, Pieris, Clearlight Diagnostics, and Inflection Biosciences.
To read more about this study, click here.