NOVEL THERAPEUTIC AGENTS FOR THE TREATMENT OF TRIPLE-NEGATIVE BREAST CANCER

Triple negative breast cancers (TNBCs) constitute approximately 12-17% of all breast cancers. Unlike patients with other breast tumor types, systemic treatment options for women with TNBC are limited, and these patients have increased rates of relapse and metastasis. One of the primary reasons for disease recurrence of TNBC is thought to be due to tumor initiating cells, or breast cancer stem cells (BCSCs), a sub-population of cells that resides within the tumor itself. These cells, which are resistant to standard chemotherapeutic and radiation therapies, are long-lived, have the ability to self renew and initiate/promote tumor development in mouse models. Molecularly, BCSCs are generally defined as CD44+CD24-EpCAM+ and/or have high levels of aldehyde dehydrogenase 1 (ALDH1^hi) enzyme activity. The expression of cell surface markers in BCSCs is significant, as they tend to define tumor phenotypes and predict treatment outcome and recurrence. Although the molecular basis that underlies disease relapse is not precisely defined, conventional chemo- and radiotherapies have been shown to cause an enrichment of BCSCs following treatment, suggesting that BCSCs are resistant to many of the currently available treatment modalities.

In an attempt to understand the molecular basis of TNBC and its resistance to traditional therapies, we designed an approach where we combined the identification of “oncogenic kinases” with drug discovery. Our compound library consists of approximately 3,000 ATP-mimetics and we tested this select group of compounds to determine if any could preferentially induce the death of BCSCs purified. This strategy identified ON108600, which showed remarkable toxicity towards tumor cells with little toxicity to normal cells. Kinase assays revealed that ON108600 is an inhibitor of CK2 a1, a 2, DYRK 1A, 1B and DYRK2. CK2 is over-expressed in cancer stem cells and its expression is associated with a poor prognosis. DYRK1 A&B have been shown to enable cancer stem cells to remain in a state of quiescence. This quiescent state allows tumor cells to escape from the effects of radiation and chemotherapy, and it is our hypothesis that selective kinase inhibition by ON108600 blocks the ability of BCSCs to become quiescent, forces their progression through the cell cycle arrest and ultimately to undergo apoptosis. We are currently investigating the effect of ON018600 and other analogs as single agents and in combination therapy using patient-derived xenograft (PDX) models of TNBC from drug resistant, post-chemotherapy tumor specimens. If these studies are successful, such results could be translated to support a future clinical trial with ON108600 to treat patients with TNBC who have an incomplete response to standard neoadjuvant chemotherapy.