Dual inhibition of PARP and STAT3 as a novel therapeutic approach for triple-negative breast cancer - Project Summary Triple-negative breast cancer (TNBC) is highly aggressive and is associated with poor clinical outcomes. TNBC is a major cause of death among breast cancer patients and is the only subtype of breast cancer that still has few effective therapeutic options. This study addresses this critical medical need by co-targeting poly (ADP- ribose) polymerase (PARP) and STAT3 in both BRCA-mutant and BRCA-proficient TNBC cells. TNBC frequently harbors BRCA mutation, which results in dysfunctional DNA repair mechanisms. PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, resulted in synthetic lethality and augmented TNBC cell death. In addition, recent reports indicate that PARP inhibitor in combination with a few drugs that can induce a BRCAness phenotype, is also effective in BRCA-proficient cancer cells. However, treatments with single-agent PARP inhibitor are not durable, leading to resistance to therapy and disease progression. TNBC cell lines secrete the highest levels of Interleukin-6 (IL-6) compared to other subtypes of breast cancer cell lines, and IL-6/STAT3 signaling confers resistance to anti-cancer drugs. In addition, our novel preliminary results demonstrate that the PARP inhibitor talazoparib can induce the IL-6 and phosphorylated STAT3 levels in TNBC cells, and talazoparib-treated TNBC cells could potentially become more resistant to talazoparib therapy by augmenting the IL-6/STAT3 axis and targeting STAT3 may potentiate TNBC cells to talazoparib therapy. This is supported by STAT3 siRNA can sensitize TNBC cells to talazoparib. Our central hypothesis is that dual inhibition of PARP and STAT3 by talazoparib and LLL12B combinational therapy is an effective approach to inhibit tumor growth, recurrence, and metastasis in both BRCA-mutant and BRCA-proficient TNBC cells. This hypothesis is supported by our novel preliminary results that (1) STAT3 inhibitor LLL12B and STAT3 siRNA can induce a BRCAness phenotype in BRCA-proficient TNBC cells, supporting PARP inhibitor therapeutic utility in BRCA-proficient TNBC as well when combined with LLL12B, and (2) the combination of talazoparib with LLL12B synergistically inhibits cell viability and significantly inhibits cell migration of BRCA-mutant and BRCA-proficient TNBC cells. We will test the hypothesis by two specific aims: (I) Evaluate the activity of talazoparib and LLL12B combination in inhibiting BRCA-mutant TNBC tumor expansion, recurrence, and metastasis using orthotopic mouse tumor models in vivo. (II) Evaluate the efficacy of talazoparib and LLL12B combination in inhibiting BRCA- proficient TNBC tumor growth, recurrence, and metastasis using orthotopic and syngeneic mouse tumor models in vivo. This study is novel and significant because it seeks to extend current PARP inhibitor treatment, which is only limited in BRCA-mutant TNBC into synergistically co-targeting PARP and STAT3 in both BRCA-mutant and BRCA-proficient TNBC. If successful, our long-term objective of translating this novel therapeutic approach of talazoparib and LLL12B combination into clinical evaluation has a potential to improve patient care and survival for women that are affected by BRCA-mutant and BRCA-proficient TNBC.
