In contrast to patients with hormone receptor- and HER2-positive breast cancers, triple-negative breast (TNBC) cancer patients have limited therapeutic options. Nowadays, TNBC therapy consists of classical chemotherapy in combination with surgery/radiotherapy and, more recently, immunotherapy. However, this therapeutic approach has limited efficacy, with a median survival of 10.2 months only.

Recent insights have shown that the availability of amino acids (AA) is a rate-limiting factor for tumor growth, malignant progression, and the therapy response of multiple cancer subtypes. Due to their high proliferation rate and/or because of oncogene-induced metabolic rewiring, cancer cells are unable to produce sufficient levels of AA and need a continuous supply of these essential building blocks though dietary intake. Responding to low intracellular AA levels, cancer cells activate an elaborate transcriptional program, referred to as amino acid stress response (AAR) signaling pathway, to regain cellular AA homeostasis and overcome temporal shortages. Our preclinical research using mammary carcinoma mouse models has shown that the inhibition of the AAR pathway can significantly suppress not only the growth of the primary tumor but also their metastatic spreading. In this project, we aim to further validate this novel promising treatment approach for TNBC and compare its effects to the first line therapies that are currently used in the clinic. Potential synergy with currently used standard therapies will also be evaluated. Next to this therapy efficacy study, we aim to perform a detailed biomarker analysis to evaluate whether all or only a fraction of TNBC patients may benefit from this. Furthermore, we will engage in a veterinary clinical trial in a cohort of cats with mammary adenocarcinoma, known to be TNBC in the vast majority of cases, as a preparation for starting a phase I clinical trial in humans.