Targeting Fatty Acid Synthase: A mechanism-guided approach to develop a novel therapeutic intervention for drug-resistant breast cancer

For the approximately 20% of patients with breast cancer that are HER2-positive, the combination of trastuzumab (also called Herceptin) with taxane-based chemotherapy, such as paclitaxel, has been the cornerstone of systemic therapy for the past two decades. Unfortunately, many patients, even with initial favorable response, will develop resistance to this treatment, and novel therapies to overcome this obstacle are urgently needed. Drug-resistant breast cancer is associated with higher rates of relapse in those previously treated for early-stage disease and with shortened survival for those with incurable metastatic disease. The vast majority of current investigational studies to address trastuzumab resistance are directed to HER2 signaling networks. In our approach to this clinical dilemma, we have chosen a new angle of study aimed toward cancer metabolism and its role in the development of drug resistance. Neglected in the past, cancer metabolism has recently attracted increasing attention because of gains in our understanding of its impact on tumorigenesis, progression, and metastasis. Furthermore, widely documented crosstalk and co-regulation of metabolic enzymes and receptor signaling networks, including HER2, have allowed metabolic modulators to emerge as promising new targets for breast cancer therapy.

In this context, we have demonstrated that fatty acid synthase (FASN), a key regulator for lipid synthesis, is upregulated in metastatic breast tumors and absent in normal breast tissue; thus, drugs that target FASN would be specific for cancer cells and spare normal healthy cells of any toxicity. High tumor levels of FASN are associated with high tumor levels of HER2, and our previous studies suggest approximately 30% of HER2+ breast cancers have high tumor FASN expression. Moreover, we have demonstrated that inhibition of FASN increases tumor cell death and reduces tumor growth and metastasis. Importantly, we have demonstrated in HER2+ breast cancer cells that are resistant to trastuzumab and paclitaxel that FASN inhibition can restore sensitivity to each of these agents.

Despite enormous interest in FASN as a molecular target for cancer therapy, none of the early generations of FASN inhibitors developed entered into human studies due to severe toxicity or lack of efficacy. Now, in collaboration with 3-V Biosciences, we have a promising, first-in-class FASN inhibitor, TVB-2640, in our hands, and it has displayed a favorable safety profile alone and in combination with paclitaxel in an ongoing Phase I clinical trial (NCT 02223247).

Our proposal is highly innovative for its focus on the untapped potential of FASN inhibitors in the treatment of drug-resistant breast cancer, and specifically trastuzumab- and taxane-resistant HER2+disease. Currently, there are no drugs in development or Food and Drug Administration-approved for breast cancer that target cancer metabolism or that can reverse resistance to trastuzumab or other HER2-directed therapies. We propose over the 5-year research period to perform a Phase II clinical trial of TVB-2640 in combination with paclitaxel and trastuzumab in HER2+ metastatic breast cancer resistant to trastuzumab and taxane-based chemotherapy. Embedded in the trial are important safety evaluations as well as a panel of rich biomarker studies that will allow for the evaluation of FASN levels in blood and tumor tissue and their association with prognosis and response to TVB-2640. Finally, we will conduct breast cancer cell line experiments to delineate how FASN inhibition promotes cancer cell death by shutting down cell survival pathways and animal studies to evaluate the anti-tumor activity of TVB-2640 with Bcl-2 antagonists, a novel combination that targets both cancer metabolism and cancer cell survival pathways.

Our proposed studies allow for rapid translation of FASN inhibitors into the clinic, and if successful, they would provide tremendous benefit for patients with HER2+ metastatic breast cancer with immediate potential to be further studied in combination with other HER2-directed therapies and in women with HER2+ early-stage breast cancer. Beyond this, we project future clinical trial opportunities to study TVB-2640 in endocrine-resistant, hormone receptor positive disease and in taxane-resistant, triple-negative disease. This research has the potential to develop the first breast cancer therapeutic that targets cancer metabolism. Successful completion of these studies would have an immediate impact to improve and extend the lives of tens of thousands women each year whose breast cancer fails to respond to standard therapies.