The majority of breast cancer (BC)-associated deaths are a direct result of invasive progression and metastasis developed in other organs such as the brain, bones, lungs, or other organs. An estimated 50 -80% of invasive BC patients will develop metastasis, resulting in a sharp decrease of 5 -year survival rate from 99% in patients with localized BCs to 27% in patients with distant metastasis. The only available targeted therapies for metastatic BCs (MBCs) are Selective Estrogen Receptor (ER) Modulators (SERMs) and Aromatase Inhibitors (AIs), which are only effective in about half of ER-positive BC patients. There are currently no other available targeted therapies for nonresponsive/resistant ER-positive BCs and all ER-negative BCs. These facts manifest the urgent need for identifying non?ER-based molecular targets and developing targeted therapies to block the progression of various subtypes of BCs to metastatic diseases. BC cells have abnormal glycolysis and the proliferating BC cells rely on dysregulated glycolysis, therefore sensitive to inhibition of glycolysis. Triple- negative BC (TNBC), the most aggressive and highly metastatic subtype of BC, was found to have increased glucose uptake, thus supporting the notion that disturbance in glucose metabolism is linked to TNBC carcinogenesis. Therefore, development of agents targeting aberrant glucose metabolism may offer alternative and potentially more effective approach for treating metastatic BC (MBC). To address this pressing need, we recently developed HJC0152 as a putative glucose metabolism modulator for treating MBCs and as molecular tool to elucidate the metastasis determinants and associated mechanisms that drive BC metastatic progression. In preliminary studies, HJC0152 was found to suppress cancer progression, inhibit cancer cell motility, block lung metastasis development, and inhibit tumor local invasion. Our central hypothesis is that HJC0152 targets key metabolism enzyme(s) to modulate glucose metabolism and suppress BC cell motility and BC metastatic progression.
Three specific aims are proposed.
In Aim 1, we will assess HJC0152?s efficacy in regressing the growth of MBCs, blocking lung metastasis development from MBCs, and prolonging the lifespan of MBC - bearing animals in vivo.
In Aim 2, we will assess HJC0152-targeted metastasis determinant proteins and optimize HJC0152 to enhance the overall drug development profiles. In preliminary studies, we have identified high - confidence targets including ARG that may directly interact with HJC0152.
In Aim 3, we will define and validate key metastasis determinant proteins mediating the anti-metastatic effect of HJC0152. The ultimate goal is to develop an innovative, non?ER-based therapy to inhibit existing metastasis and reduce/block new metastasis to achieve significantly improved prognosis for patients with MBCs. At the completion of this project, it is expected that the anti-metastasis and life-prolonging efficacy of HJC0152 will be determined and high-confidence target will be identified and validated in MBCs, thereby making HJC0152 ready to be advanced into Investigational New Drug (IND) registration for further preclinical and clinical development for treating MBCs.
Metastasis accounts for 90% of cancer-associated deaths and results in a 40,000 yearly death toll from breast cancer (BC) in U.S., however, to date there is no effective targeted therapy available for metastatic BCs. In preliminary study, we found that our newly developed orally active glucose metabolism modulator, HJC0152, significantly blocked metastasis of highly aggressive BCs in animal models via targeting aberrant glucose and energy metabolism. To provide the foundation and rationale to target glucose metabolism pathway as a new strategy for treating metastatic BC and bring novel anti-metastatic drugs for human trials, we propose to characterize the therapeutic efficacy for HJC0152 in clinically relevant settings, define the HJC0152-targeting metastasis-associated molecules important in NC progression and metastasis, and identifying the HJC0152- interacting targets that mediate HJC0152?s anti-metastatic efficacy.
