Dysregulation of the cell cycle is a hallmark of human cancer, in particular mantle cell lymphoma (MCL), wherein cyclin D1 is aberrantly expressed due to chromosomal t(11;14) translocation. Together with overexpression of cyclin-dependent kinase (CDK)4, this leads to cell cycle acceleration and unrestrained proliferation of tumor cells that underlies disease progression. Since MCL remains incurable, novel therapies that control the cell cycle are urgently needed. Using PD0332991 (PD), the only known selective and potent inhibitor of CDK4/CDK6 that is also orally bioavailable and reversible, we have developed a novel strategy to both control the cell cycle in tumor cells and sensitize them to cytotoxic killin. We have demonstrated, for the first time, that 1) selective inhibition of CDK4/CDK6 leads to early G1 arrest and, 2) upon release of the G1 block, a synchronized progression to S phase occurs;3) prolonged G1 arrest (pG1) sensitizes tumor cells to cytotoxic killing, and 4) pG1 sensitization to cytotoxic killing is amplified in the subsequent S phase synchronization (pG1-S). We hypothesize that this increased sensitivity to cytotoxic agents is due to halting of gene expression in pG1 and incomplete restoration of scheduled gene expression despite cell cycle progression after the release of the G1 block. To test this hypothesis in the context of clinical response, we demonstrated in the first Phase I, single-agent clinical study of PD in human cancer that PD preferentially and potently inhibited CDK4/CDK6 in MCL cells in relapsed/refractory patients, with an excellent toxicity profile and an encouraging clinical response. These findings have been confirmed in an ongoing Phase I clinical study targeting CDK4/CDK6 with PD in combination with the proteasome inhibitor bortezomib (PDBo) in MCL and in multiple myeloma (MM). Preliminary whole transcriptome sequencing (WTS) of MCL cells from serial biopsies has further revealed that 21 of the genes suppressed in pG1 in clinically responsive patients were conversely activated in the non-responding patients (N=6), and seven of them overlap with genes that were oppositely regulated in pG1 in clinically responding vs. non- responding patients in the parallel PDBo clinical study in MM. These novel findings are consistent with a unified underpinning mechanism of key hub genes for pG1 sensitization, and suggest a unique opportunity to identify genes that mediate pG1 sensitization to cytotoxic killing and differential clinical response. In this study, we propose to define pG1-sensitizing genes by expanding and deepening integrated WTS as well as whole exome sequencing of serial MCL tumor biopsies from the PDBo clinical study in the context of the clinical response (Aim 1) in conjunction with functional validation of candidate biomarkers ex vivo (Aim 2). We believe that successful completion of the proposed study will define biomarkers that differentiate clinical responses to pG1 sensitization in the CDK4/CDK6-based therapy in MCL, and may reveal a common regulatory framework for cell-cycle based cancer therapies.

Public Health Relevance

Loss of cell cycle control is central to the development and progression of human cancer. We have developed the first therapy that both effectively inhibits tumor cell division and sensitizes them to killing by cancer drugs. By identifying the genes that are necessary to specifically sensitize tumor cells to die by whole genome RNA and DNA sequencing, we hope to significantly advance cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA176362-02
Application #
8625288
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Jessup, John M
Project Start
2013-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$165,409
Indirect Cost
$67,534
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065