Ribociclib&Belinostat In Patients w Metastatic Triple Neg Breast Cancer & Recurrent Ovarian Cancer w Response Prediction By Genomics

We hypothesize that ribociclib plus belinostat will be a well-tolerated and demonstrate activity in women with metastatic triple-negative breast or recurrent ovarian cancers.

This trial combines two targeted agents, a CDK inhibitor and a lysine deacetylase (DAC) inhibitor for use as the first targeted treatment for metastatic triple-negative breast cancer. This in itself would be a leap forward for women who currently endure sequential treatment with cytotoxic chemotherapies. However, we will also be using samples from this trial in NIH-funded research on clonal evolution and geographic heterogeneity in breast cancer. Blockade of CDK4/6 and of lysine deacetylases (DAC) are both promising treatments for breast cancer. DAC inhibitors have been shown to have single-agent activity against triple-negative breast cancer in vivo, possibly through decreasing EMT, decreasing migration, and decreasing metastasis \[6, 7\] CDK4/6 inhibitor monotherapy causes cell cycle arrest and tumor regression in triple-negative breast cancer models. \[8, 9\] However, neither approach has been successfully translated into clinical use as a monotherapy.

There are several lines of evidence demonstrating that inhibiting DAC increases the sensitivity of breast cancer to CDK4/6 inhibition. Recently, we showed that inhibitors of cell cycle progression, including CDKN1A, CDKN1C, CDKN2B, and CDKN2D, are increased by DAC inhibition in breast cancer cell lines, including triple-negative cell lines. \[10\] Others have shown cell cycle arrest by DAC inhibitors due to increases in p21 or decreases in CDK2 and cyclin A. \[11-13\] We also see an increase in RB1 expression in breast cancer cell lines. In the TCGA breast cancer analysis, RB1 was frequently down-regulated but not mutated or lost in triple-negative breast cancer. \[14\] Therefore, we hypothesized that DAC inhibition would increase the sensitivity of breast cancer to CDK4/6 inhibition. We first tested this hypothesis in a small panel of cell lines. We showed and published that all showed synergy between a CDK4/6 inhibitor (PD-0322991) and DAC inhibitors. \[10\] Since then, we have tested the combination of the DAC inhibitor vorinostat and the CDK4/6 inhibitor PD-322991 in a larger panel of cell lines and have shown at least additivity in most triple-negative cell lines. Indeed, it seems that those cancers least sensitive to CDK4/6 inhibition may benefit the most from co-treatment with a DAC inhibitor.

Recently, we investigated ribociclib and belinostat in six triple-negative breast cancer cell lines. All 6 cell lines showed growth inhibition with belinostat and panobinostat. Synergy was seen in four of the six cell lines at multiple doses.