ER+ Breast Cancer
About 70-80% of breast cancers are characterized by the expression of the estrogen receptor (ER). The USA alone has about 250,000 new cases every year (2016), and ER+ breast cancer is part of a breast cancer market that is expected to grow ~6% per year, reaching over $13B by 2020. Constitutive ER signaling confers a proliferative advantage to cancer cells, hence the development of inhibitors that inhibit the synthesis of estrogen or the ER itself. Despite potent clinical efficacy, resistance to these inhibitors occurs frequently and involves the recovery of ER signaling in 30% of cases, highlighting the need for other therapies that interfere with ER synthesis and signaling. Recently, BET inhibitors have been shown to inhibit ER transcription, which in turn reduces ER protein and signaling while inhibiting cell proliferation and promoting cell death (apoptosis).
ZEN-3694 showed efficacy in various models of ER+ breast cancers, including in models that are resistant to ER inhibitors. ZEN-3694 down-regulated ER signaling, as well as several pathways associated with resistance to ER-based therapies in the clinic. These results suggest that ZEN-3694 could potentiate existing treatments for ER+ breast cancer patients by offering a novel approach to target ER signaling.
Triple-Negative Breast Cancer (TNBC)
TNBC represents 10% – 20% of breast cancer diagnoses (~30,000 patients annually in the United States) and is part of a breast cancer market that is expected to grow ~6% per year, reaching over $13B by 2020. TNBC is defined as estrogen and progesterone receptor negative and lacking overexpression of HER2. Unlike ER+ and HER2+ breast cancer, no targeted therapies currently exist for TNBC. Patients must undergo aggressive chemotherapy which achieves a good initial response rate. However, five year recurrence rates are high (34%), and effective second line therapy is not clearly defined, creating a challenging unmet clinical need. TNBC is a highly heterogeneous, physiologically complex disease and significant advances have been made in identifying subclasses based on gene expression and mutation status. ZEN‑3694 has been shown to be effective across all subtypes of TNBC cell lines, indicating that ZEN-3694 could improve existing therapies across this patient population. The tumor microenvironment also plays a central role in disease progression and resistance to current therapies, and ZEN-3694 inhibits several of these players, suggesting that ZEN-3694 could affect not only the TNBC tumor itself, but also the tumor environment.
Lung cancer is the most common cancer in the world, and with approximately 220,000 new cases per year in the USA alone, remains the leading cause of death from cancer in both men and women. The global market for lung cancer therapeutics is expected to reach $9 billion by the end of 2021. Despite the fact that chemotherapies, immunotherapies, and several targeted agents are approved for lung cancer, the majority of metastatic patients quickly relapse and succumb to the disease. Lung cancer can be divided into two main subtypes, SCLC (small cell lung carcinoma) and NSCLC (non-small cell lung carcinoma), both of which are sensitive to BET inhibition. While SCLC only accounts for about 15% of total lung cancers, it comprises the worst prognosis and has no targeted therapies available. SCLC cell lines are widely sensitive to BET inhibition, and BET inhibitors target defined oncogenic drivers in this population. NSCLC contains the subgroups adenocarcinoma and squamous cell carcinoma. Within this population, there are several targeted therapies and immunotherapies approved. There is growing evidence that BET inhibitors may work to improve the frequency and duration of responses in these patients. In particular, BET inhibitors synergize with EGFR inhibitors, and may also target mechanisms of resistance to these drugs. Furthermore, ZEN-3694 targets the population of NSCLC driven by the oncogenes KRAS and MYC, which are often considered undruggable.