Uncontrolled cellular proliferation is a hallmark of cancer. Dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression is a key mechanism in many cancer pathologies. The first-generation of nonselective CDK inhibitors, designed to inhibit this proliferation, showed high degree of toxicity and lacked efficacy. In contrast, a new generation of selective CDK4/6 inhibitors, including small molecules such as ribociclib, abemaciclib and palbociclib,has enabled tumor types in which CDK4/6 has a pivotal role be targeted with improved effectiveness, and fewer adverse side effects. However, CDK4/6 inhibitors are limited in their single-agent efficacy and there is emerging evidence acquired resistance for these small molecules. Recent research also suggests that long-term treatment with CDK4/6 inhibitors can hinder the antitumor immune response by causing senescence in normal cells. Thus, there is need to develop a new class of selective CDK4/6 inhibitors.
Summary of Invention
Dr. Wafik El-Deiry and his team at the Fox Chase Cancer Center have identified four unique microRNAs (miRNAs) that inhibit the activity of CDK4/6. Unlike the small molecule approach where they target CDK4/6 directly, these miRNAs function by silencing the mRNA for production of CDK4/6 thereby reducing the protein levels of CDK 4/6 in cancer cells. The miRNAs display significant anti-proliferative effects in colorectal cancer, pancreatic cancer and melanoma cell lines. In addition, the miRNAs also engage the apoptosis pathway by down-regulating anti-apoptotic markers such as XIAP, BClxL and FOXM1. Synergies between these miRNAs and drugs currently used in treatment of colorectal cancer such as irinotecan and 5-fluorouracil have been observed.
Reference: Lulla A.R. et al., “miR-6883 Family miRNAs Target CDK4/6 to Induce G1 Phase Cell-Cycle Arrest in Colon Cancer Cells” 2017, Cancer Res. Dec 15; 77 (24): 6902-6913. https://www.ncbi.nlm.nih.gov/pubmed/29061672
- Broad-range and yet specific targeting of multiple oncogenes in cell cycle and apoptosis pathways
- New line of therapeutics, and/or an alternate adjuvant therapy for cancers that dependent on the activity of CDK4/6 such as colorectal, breast, lung cancers, melanoma and leukemia
Patent Status: Patent application filed
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Inna Khartchenko, MS, MBA
Director, Technology Transfer
E-mail: [email protected]