Drug Design & Development

Targeted Therapy against Triple Negative Breast Cancers

Breast cancer is the most diagnosed cancer and the second leading cause of mortality. Triple-negative breast cancer (TNBC) is characterized by the absence of receptors for estrogen and progesterone as well as lack of HER-2 gene. These tumors are enriched in cancer stems cells and exhibit resistance to most treatments and chemotherapy. TNBC is more prevalent in younger females and accounts for about 10% to 20% of breast cancer incidence with poor prognosis.** **Importantly, to date, no efficient therapy exists for this type of cancer. In addition, it was reported that the chemotherapy drugs enriched CSCs in TNBC patients. Hence it is crucial to define new treatment options for these patients to prevent cancer relapse, drug resistance and metastasis.

We recently uncovered new role for CDK4-dependent in regulating cancer stemness and as a novel prognostic marker in TNBCs. The expression of CDK4 in TNBC patients correlates with worse clinical outcome. Moreover, we found that blocking this pathway, using a specific inhibitor of CDK4/6 (Palbociclib) could eliminate breast cancer stem cells (CSC) but also chemotherapy resistant breast cancer cells in TNBCs. These exciting results highlight CDK4 as promising therapeutic targets for the development of new therapies against TNBCs.

While existing pan-CDK4/6 inhibitors showed promising results on primary tumor growth when used in combination therapy in hormone receptor positive (HR+) tumors, they failed clinical trials for TNBC. We made inroads into understanding CSC biology in breast cancer and found high expression of the cyclin-dependent kinase 4 (CDK4) to correlate with poor overall and relapse-free survival outcomes in metastatic TNBC patients. We further showed that silencing CDK4, but not the closely related kinase CDK6, efficiently reduced CSC numbers in TNBCs and reversed their basal mesenchymal phenotype, highlighting CDK4 as a promising therapeutic target in CSC-enriched TNBC. These studies led to the recent development of new kinase inhibitors that preferentially target CDK4 over CDK6. In particular, using molecular modeling approaches, we generated a lead compound (KP108) which not only has high selective affinity for CDK4 (over CDK6), but also exhibits a dual targeting capability by blocking the cell cycle (G2/M phase) PLK1 kinase. Our lead showed great efficacy and sustained activity in blocking primary breast tumor formation and lung metastasis. It also showed a broader scope of activity (i.e. RB null patients), compared to existing drugs, further expanding its potential clinical use. Our preliminary results also showed that our lead could efficiently prevent tumorigenesis in prostate and pancreatic cancers. Thus, while initially targeting the breast cancer therapeutic area, with a proposed specific indication for metastatic HER2+ and TNBC tumors, KP108 would also benefit other types of solid tumors metastatic cancers. (USPTO patent filing EFS ID 40804961; Application Number 17066824; Title: Single molecules having mixed CDK4, CDK6, PLK1 targeting properties. We are currently optimizing our lead compound, assessing PK/PD/ADME components to further promoting its their transition to Phase I clinical trials.