Development of Novel Inducers of Nonapoptotic Cell Death to Target TNBC
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive, metastatic, recurrent, and fatal subtype of breast cancer, accounting for one-fourth of all breast cancer deaths. TNBC is difficult to treat due to the absence of three key targetable receptors; the estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. Anthracycline (e.g., doxorubicin) and taxanes (e.g., paclitaxel) based regimens are standard treatments for TNBC. However, this therapy becomes ineffective in many patients due to undesirable adverse effects and the development of chemoresistance. Patients with residual, resistant tumors have a 6-times higher rate of distant recurrence and are 12 times more likely to die within a year. The treatment of chemoresistant TNBC tumors is particularly challenging due to the overexpression of efflux transporters, increased DNA repair, and the occurrence of genetic mutations that decrease the likelihood of apoptosis. In our efforts to surmount TNBC resistance, we discovered a novel class of thieno-pyrimidin-4-yl-hydrazinylidene (TPH) compounds that in the nanomolar range, selectively elicited a unique, caspase-independent, non-autophagic, necroptotic- inducing (NANI) cell death in TNBC, as well as in doxorubicin- and paclitaxel-resistant TNBC/resistant(R) cells. The most promising TPH compound, TPH104, selectively induced receptor interacting protein kinase 1 (RIPK1)-mediated necroptosis, while potently inhibiting the phosphorylation of dynamin-related protein 1 (Drp1), which promotes autophagy by producing mitochondrial fission, allowing for the significant proliferation of TNBC cells. TPH104 in combination with doxorubicin and paclitaxel synergistically inhibited TNBC and TNBC/R cells. TPH104 also significantly reduced the dose-reduction index (i.e., the toxicity of doxorubicin and paclitaxel) and reversed TNBC/R resistance mediated by ABCB1 and ABCG2 transporters. This led us to determine whether a multimodal, non-apoptotic approach can overcome chemoresistance in TNBC patients. Therefore, we hypothesize that new opportunities to treat chemoresistance in TNBC patients could result from using TPH104 as a probe to understand the phenomenon of non-apoptotic NANI processes and to identify the structural requirements for targeting TNBC cancers refractory to apoptosis. Based on this hypothesis, in Aim 1, we will determine the protein target(s) of TPH104 using several unbiased approaches and further determine the role of Drp1 in NANI cell death. In Aim 2, we will determine the structural requirements of TPH compounds required to induce NANI by using shape-based modelling, core-hopping, retrosynthetic, and bioisosteric approaches. In Aim 3, we will evaluate, in mice, the pharmacokinetic profile (i.e., absorption, distribution, metabolism, and excretion (ADME)) and toxicity of the lead TPH analogs, and their anti-tumor efficacy in mice bearing patient-derived TNBC xenografts. The findings of these studies will allow us to understand the biology of caspase-independent NANI cell death by this new class of small molecules that, in the future, may be beneficial for treating patients with drug-resistant and aggressive TNBCs. In line with mission of the Breast Cancer Research Program, the successful outcome of this study will address two main overarching challenges in the breast cancer landscape: 1) why tumors re-emerge and how to prevent recurrence; and 2) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival, leading to a substantial reduction in breast cancer deaths by 2026.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110053
Entities
People
- Amit K Tiwari
Organizations
- United States Army
- University of Toledo Health Science Campus