In a study published in Cancer Research, BCRF researchers Drs. Jill Bargonetti and Funmi Olopade report a possible new treatment strategy that targets vulnerabilities in triple-negative breast cancer (TNBC), a particularly aggressive form of the disease with limited treatment options. This study shows that two proteins associated with TNBC tumor growth—mtp53 and PARP1—may also be biomarkers for targeted treatments.
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Approximately 15 percent of all breast cancers are classified as TNBC, a form of the disease that lacks estrogen and progesterone receptors and HER2 protein. Because TNBC tumors lack these factors, they cannot be treated with hormone therapy or HER2-targeting drugs. TNBC disproportionately affects younger women and those of African or Hispanic descent, and it is the most commonly diagnosed form of breast cancer in BRCA1 mutation carriers. Chemotherapy is standard treatment for TNBC and, in patients with BRCA mutations, targeted drugs called PARP inhibitors are also used.
The importance of mtp53 and PARP1 proteins in TNBC
Over 80 percent of TNBC tumors express a mutated form of p53 (designated mtp53). In its normal form, p53 suppresses tumor development by preventing cells with unrepairable DNA damage from dividing and passing damaged DNA to daughter cells. Contrary to its normal function, mtp53 promotes not only tumor growth, but tumor cell invasion and drug resistance.
In a normal cell, PARP1 protein acts as a first responder that detects DNA damage and facilitates its repair. PARP inhibitors directly inhibit the PARP1 protein so that tumor cells cannot repair damaged DNA and, therefore, cannot grow.
Previous work from Dr. Bargonetti’s lab indicated that, in advanced TNBC, the expression of mtp53 is associated with sensitivity to PARP inhibitors. At a BCRF research event, Dr. Bargonetti connected with fellow BCRF researcher Dr. Funmi Olopade, knowing Dr. Olopade worked with TNBC patients.
“I asked Dr. Olopade if she’d like to collaborate on a study to determine whether the mtp53-PARP association was prevalent in TNBC patients,” Dr. Bargonetti said. “This study came out of those conversations. Our data strongly suggest that mtp53-PARP is a biomarker for responsiveness to anti-PARP therapy.”
The results of the study
Using a variety of laboratory models and methods, the BCRF researchers found that mtp53 interacts with PARP1 proteins to facilitate the DNA repair process, thus promoting the growth of TNBC tumors. This interaction, however, made the cells exquisitely sensitive to the combination of a PARP inhibitor, talazoporib (TALZENNA™) and a DNA damaging drug, temozolomide (TEMODOR ®). These agents appear to act synergistically to lock PARP1 on damaged DNA, thereby preventing further DNA repair.
In addition, the researchers examined clinical tumor samples and found evidence for mtp53 and PARP1 as dual biomarkers to identify patients with TNBC who may respond to treatment with this combination of chemotherapy drugs.
What this means for TNBC patients
These findings expand our understanding of TNBC and may result in better treatment strategies for this aggressive disease. While these studies are in early phases and additional studies are ongoing, both drugs are already FDA approved, which may increase the chance that this combination approach can move into clinical trials quickly.
“This paved the way for an NIH award to explore mtp53-PARP in a much larger cohort of TNBC patients,” Dr. Bargonetti said. “Our BCRF-supported work is gaining wider attention in the field.”
Dr. Bargonetti is the recipient of the 2020 Estée Lauder Companies’ Brands Award in Memory of Evelyn H. Lauder. Dr. Olopade is the recipient of the 2020 Estée Lauder Companies’ North America Manufacturing & Distribution and Global Research & Development Award, as well as the Ulta Beauty Award.
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