Enhancing efficacy of cyclin-dependent kinase inhibitors in diffuse large B-cell lymphoma
Alexey Danilov
PhD, MDBeckman Research Institute of the City of Hope
Project Term: October 1, 2021 - September 30, 2023
Nearly half of patients with diffuse large B-cell lymphoma (DLBCL), ultimately fail current therapies and die from their disease. Selective targeting of cyclin-dependent kinase 9 (CDK9) is a promising strategy, as evidenced by potent anti-tumor effects in preclinical models of DLBCL. Yet tumors evade therapy by developing resistance. This proposal seeks to both elucidate and circumvent the oncogenic events underlying this resistance in order to offer novel therapeutic approaches to treat DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. It is the most common lymphoid neoplasm and accounts for more than 20,000 cases per year in the U.S. Only half of patients treated with chemo-immunotherapy regimens achieve complete remission, highlighting an urgent need for more effective therapies. In this context, selectively targeting cyclin-dependent kinase-9 (CDK9) constitutes a promising strategy. CDKs are serine/threonine kinases that regulate cell-cycle progression, although some, such as CDK9, function as gene transcriptional regulators. Despite proven anti-tumor activity, non-selective pan-CDK inhibitors have not been successful in the clinic, mainly due to excessive toxicities that do not allow dosing at therapeutic levels. Hence, developing selective CDK inhibitors with fewer side effects has been the object of intense research. We have shown that targeting of CDK9 has potent anti-tumor effects in pre-clinical models of DLBCL and leads to rapid downregulation of the transcriptional programs governed by the MYC oncogene. However, CDK9 inhibition does not completely halt tumor growth, due to the development of resistance. Here, we build on our recent findings that following CDK9 inhibition certain genes undergo recovery, which we suspect contributes to drug resistance. In this proposal, we will harness innovative techniques, such as CRISPR-Cas9 library screening, ATAC-Seq and ChIP-Seq, to achieve three Specific Aims. In Aim 1, we will identify the oncogenic events that contribute to resistance to CDK9 inhibition in DLBCL and pursue the most promising gene candidates: We will also investigate how targeting CDK9 regulates packaging of genetic material. In Aim 2, we will evaluate innovative therapeutic strategies to overcome resistance to CDK9 inhibitors. In Aim 3, we will confirm the functional significance of our findings by analyzing clinical specimens from patients treated with the CDK9 inhibitor voruciclib in a clinical trial. The proposed experiments will elucidate the mechanisms and provide therapeutic strategies to overcome resistance to CDK9i. Our ultimate goal is to advance the therapeutic development of CDK inhibitors in lymphoma and more broadly in other types of cancer.