Background: Trastuzumab in combination with taxane-based chemotherapy has an established clinical benefit for the treatment of both HER2+ early-stage breast cancer (EBC) and metastatic BC (MBC). However, de novo and acquired resistance to trastuzumab and other HER2-targeted therapies remains a challenge and unmet clinical need in the care of patients with HER2+ BC. Novel approaches to overcome resistance must be prioritized so we can further drive down relapse rates for HER2+ EBC and improve upon survival rates for those with HER2+ MBC. Given the lack of groundbreaking success with current approaches, we have pursued a more innovative angle to exploit the link between the tumor metabolic and HER2 signaling networks. Largely overlooked in the past, cancer metabolism has attracted increasing attention, and our extensive work on fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, builds a solid foundation for this proposal. FASN is highly expressed in invasive BCs while absent/low in normal breast tissues. Tumor FASN expression positively correlates with HER2 levels and poor prognosis. FASN blockade rapidly induces apoptosis in cancer cells with no effects in normal cells, implying the reliance of tumor proliferation and survival on FASN-driven endogenous fatty acid biogenesis. In turn, FASN inhibition effectively reverses oncogenic phenotypes in vitro and in vivo, and we have demonstrated that it can reverse BC resistance to several clinically relevant agents, including paclitaxel and trastuzumab. Furthermore, in vitro studies reveal a sensitizing effect of FASN inhibition to Bcl-2 inhibitors in BC cells bearing the incredible potential for this novel combination therapy to be further explored. Despite enormous interest in FASN as a molecular target for cancer therapy, clinical development of the many available FASN inhibitors has languished due to severe toxicity or lack of efficiency. Now, in collaboration with 3-V Biosciences, we have in our hands a promising, first-in-class FASN inhibitor, TVB-2640, and it has demonstrated a favorable safety profile in an ongoing Phase I clinical trial (NCT 02223247). Therefore, we hypothesize that FASN will serve as a novel prognostic marker and the FASN inhibitor, TVB2640, will restore sensitivity to trastuzumab and paclitaxel in HER2+ BC.Overarching Challenge: Cancer metabolism is necessary for tumor cells to grow, divide, remain structurally stable, and adapt to the microenvironment. Tumor growth is further perpetuated by de novo or acquired resistance to standard therapies. Currently, there are no investigational or Food and Drug Association-approved BC therapeutics that target cancer metabolic pathways or overcome trastuzumab and paclitaxel resistance. We propose to revolutionize BC therapy through the clinical study of TVB-2640 in patients with HER2+ BC that is resistant to taxane and HER2-directed therapies.Specific Aims and Study Design: We will address our hypothesis as follows: Aim 1: Assess the clinical activity of a novel FASN inhibitor, TVB-2640, in combination with paclitaxel and trastuzumab in a Phase II clinical trial of patients with HER2+ MBC resistant to taxane and HER2-directed therapy. Aim 2: Examine the clinical value of serum and tissue FASN as a novel prognostic marker in HER2+ BC. Aim 3: Define a thorough link between FASN and intrinsic apoptosis with the outstanding potential to combine FASN and Bcl-2 antagonists for future treatment of BC. The aims are designed for rapid translation into the clinic. In more detail, we will: (1) Conduct a Phase II trial combining TVB-2640 with weekly paclitaxel and trastuzumab in patients with HER2+MBC resistant to taxane and HER2-directed therapy. Based on preliminary data from the ongoing Phase I trial of TVB-2640, we predict that the combination will be safe and associated with objective tumor response. This will support further development of TVB-2640 to delay/prevent resistance to these agents in subsequent trials for all stages of HER2+ BC and other molecular subtypes of BC. (2) Perform a biomarker analysis of tumor FASN expression in prospectively collected biospecimens from Phase II trial participants. This will support FASN as a biomarker associated with poor prognosis and drug resistance, and it may identify patients who would derive benefit from FASN inhibitors. (3) Study the mechanism by which FASN inhibition enhances chemosensitivity via promotion of mitochondria-associated apoptosis. This will provide the basis for therapeutic application of pharmacological FASN inhibition in combination with Bcl-2 inhibitors for BC.Impact: Successful completion of the studies will have immediate impact to improve the clinical outcomes of patients with HER2+ BC and support future trials to target cancer metabolism and apoptotic pathways for the treatment of all molecular subtypes of drug-resistant BC.
|Effective start/end date||9/30/16 → 9/29/21|
- Congressionally Directed Medical Research Programs: $2,187,991.00