Activating TFEB to enhance the efficacy of immunotherapy for triple negative breast cancer

Promilead, Llc, Columbia SC

Investigators

Abstract

Summary: Triple negative breast cancer (TNBC) is the deadliest subtype of breast cancer. Recent success of immunotherapy, particularly immune checkpoint inhibitors (ICIs), brings new hope to TNBC patients. Indeed, TNBC tumors are the most immune cell infiltrated (“hot”) breast tumors and thus, more likely to respond to ICIs. While single-agent ICIs are largely ineffective, combining chemotherapy and ICIs improves the outcome. Chemotherapies are believed to promote antitumor immunity through both the induction of immunogenic cancer cell death (ICD) and the killing of suppressive immune cells. Currently, Keytruda is the only FDA-approved ICI for TNBC. However, only a small percentage of TNBC patients respond well to the Keytruda+chemotherapy regimens. This is largely due to: 1) the tumors are not “hot” enough and the chemotherapy drugs do not induce sufficient ICD of cancer cells, and 2) the intrinsic and/or therapy-induced immunosuppressive tumor microenvironment, which is orchestrated predominantly by tumor-associated macrophages (TAMs), diminishes the efficacy. Therefore, new strategies to improve the response of TNBC patients to ICIs are urgently needed. Over the past several years, our laboratory has discovered important tumor suppressive roles of TFEB in breast cancer. Our published data demonstrated that TFEB expression and activation favorably modulates TAM functions and thereby suppresses breast tumor growth in mouse models. We showed that TFEB expression is reduced in TAMs in human breast tumors, and analysis of human patient genome database revealed that higher expression levels of TFEB in breast tumors correlate with better patient outcome. Our new preliminary data suggest an antitumor role of TFEB expression and activation in breast cancer cells. Moreover, Dr. Yangmei Li at PromiLead LLC synthesized and characterized a small-molecule compound USCYL01 as a potent TFEB activator in MΦs and breast cancer cells. USCYL01 favorably modulates macrophage gene expression and promotes ICD of breast cancer cells. A pilot in vivo study showed that USCYL01 inhibited breast tumor growth in mice without causing any evident toxicity. Based on these exciting findings, we hypothesize that activating TFEB in breast tumors using USCYL01 can boost the antitumor immune response and enhance the efficacy of ICIs in TNBC treatment by ameliorating the immunosuppressive functions of TAMs and augmenting cancer cell ICD. Two specific aims are proposed. SA1: Evaluate the toxicity of USCYL01 in vitro and in vivo and determine its pharmacokinetic properties in mice. SA2. Test USCYL01 as an agent to enhance the efficacy of ICI+chemotherapy for TNBC. The successful completion of the Phase I studies will establish the feasibility to develop this novel TFEB activator as an add-on therapy to unleash the full potential of the ICI+chemotherapy regimens for TNBC treatment.