The cell cycle in therapy in lymphoma and myeloma
Targeting the Cell Cycle in Lymphoma Therapy Selina Chen-Kiang Weill Cornell Medical College CDK Inhibitors Non-Selective CDK4/CDK6 inhibitors Targeting multiple CDKs, some are transcription factors • Flavopiridol CDK9 • Daniciclib CDK7 Selective CDK4/CDK6 inhibitors • PD 0332991 (palbociclib) Lymphoma, Myeloma Solid tumors-Breast Cancer (ER+/HER-) –Breakthrough therapy, combination with letrozole, Phase 3 • LEE011 Breast Cancer –combination with letrozole and BYL719, Phase 3 Melanoma • LY2835219 Non-Small Cell Lung Carcinoma Breast Cancer The Cell Cycle Positive Negative Go Cyclin D + CDK4/6 M G1 G2 pS-Rb-E2F Cyclin E + CDK2 S pST-Rb CDK: Cyclin-Dependent Kinase p18INK4c (CDKN2C) E2F release p16 p15 p18 p19 p21 p27 p57 mid-G1 checkpoint Targeting CDK4/6 with PD 0332991 (palbociclib) • • • • • • Selective CDK4/CDK6 inhibitor (IC50 11 nM) Orally bioavailable pyridopyrimidine Competing with ATP for binding to the kinase site of CDK4/CDK6 Induces early G1 arrest Reversible Low in toxicity • Selectively and potently inhibits CDK4/6 phosphorylation of Rb in primary human myeloma cells (IC50 60 nM ) • Inhibits tumor growth in the NOD-SCID human myeloma xenograft models and the immune-competent mouse 5T models Fry et al., 2004, Mol Cancer Ther Baughn et al., 2006, Cancer Research Menu et al., 2008, Cancer Research Targeting CDK4/CDK6 in combination therapy CDK4/6 Inhibitor Partner agent (low dose, selective ) Weill-Cornell Mantle cell lymphoma Multiple Myeloma Mantle cell lymphoma Phase I single agent Phase I/II PD-bortezomib-Dex Phase I PD 0332991-bortezomib 2014 Mantle cell lymphoma Phase I PD 0332991-Ibrutinib Multiple myeloma Phase I PD 0332991-Lenalidomide-Dex Prolonged early G1 arrest (pG1) Hypothesis Go Cyclin D + CDK4/6 M G1 G2 PD 0332991 pS-Rb S Prolonged inhibition of CDK4/6 Prolonged early G1 arrest (pG1) Expression of only genes programmed for early G1 Sensitizing tumor cells to cytotoxic killing pG1 Hypothesis Go Cyclin D + CDK4/6 M G1 G2 PD 0332991 Reversible pS-Rb S Release of prolonged early G1 block Cell cycle synchronization incomplete restoration of scheduled gene expression Further sensitizing tumor cells to cytotoxic killing Targeting CDK4/CDK6 in Recurrent MCL Single agent PD 0332991 Phase I study • Inhibition of CDK4/CDK6 by PD 0332991 leads to prolonged G1 arrest (pG1) and increased tumor-specific cell death in MCL (n=17) • PD 0332991 (125 mg/d orally 21 of 28 d) is generally well tolerated with neutropenia, fatigue and diarrhea as most common adverse events • 1 complete response, 2 partial response, 5 SD > 1 year Leonard, et al Blood 2012 Phase I study of PD 0332991 + bortezomib in patients with recurrent MCL Biopsy ★ ★ pG1 ★ pG1-S Martin, Di Liberto, Leonard, et al, unpublished Phase I study of PD 0332991 + bortezomib in patients with recurrent MCL % change in tumor size (by patient) Martin, Leonard, unpublished Inhibition of CDK4/6 induces early G1 arrest in MCL cells of both responders and non-responders initially. Can we identify genes that differentiate sensitivity from resistance to targeting CDK4 in combination with bortezomib? M. Di Liberto, D. Chiron, C. Mason, P. Martin, J. Leonard, S. Ely, unpublished Prolonged early G1 arrest (pG1) Hypothesis Go Cyclin D + CDK4/6 M G1 G2 PD 0332991 pS-Rb S Prolonged inhibition of CDK4/6 Prolonged early G1 arrest (pG1) Expression of only genes programmed for early G1 Sensitizing tumor cells to cytotoxic killing Longitudinal Integrative analysis of whole exome-sequencing (WES) and whole transcriptome-sequencing (WTS) of serial biopsies, using cheek swab as a control. Integrative WES and WTS analysis Lymph node biopsy CD5+CD19+ isolation WES (50ng DNA) CNV SNVs WTS (100-100ng RNA) mRNA abundance Alternative splicing Only 1% of the genes that were repressed in (pG1, day 8) in clinically responding patients (R) were up-regulated in pG1 nonresponding patients (NR). Candidate biomarkers for the PD 0332991-bortezomib therapy? Differential regulated genes • Glucose homeostasis • Redox homeostasis • Cell migration Chiron, Di Liberto, Mason, Martin, et al, unpublished Targeting CDK4 in combination with bortezomib in MCL • At the optimal PD 0332991 concentration and reduced bortzomib 1 CR, 1 PR, 2 near PR (43% reduction), 1 SD, 1 PD. • Inhibition of CDK4 induces early G1 arrest that controls cell cycle gene expression in all MCL patients initially. • MCL cells express CDK4 but not CDK6, cyclin D1 but not D2 or D3 • CDK4 is a stable target- no mutation in CDK4 detected • A small number of genes are oppositely regulated in pG1 (day 8 vs day 0) in responders vs non-responders – candidate biomarkers for targeting CDK4 in combination with bortezomib. Glucose homeostasis Redox homeostasis Cell migration pG1 reprogramming MCL cells for ibrutinib inhibition of Bruton Tyrosine Kinase (BTK) Ibrutinib is effective in MCL. However, relapse is frequent and associated with aggressive proliferation and poor prognosis Relapse-specific C481S mutation in BTK in MCL --Longitudinal integrative WES and WTS analysis Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 Relapse-specific C481S mutation in BTK in MCL --Longitudinal integrative WES and WTS analysis BTK C481S mutation undetected before Ibrutinib relapse At least two mechanisms of Ibrutinib relapse - • BTKC481S mutation is detected in durable ibrutinib response (>14 or 30 months, 2/2. • However, BTKC481S mutation is absent in transient ibrutinib response (< 5months) or primary resistance (6/6) Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 • BTK is inactivated by ibrutinib in MCL cells of both sensitive and resistant patients in vivo • PI3K-AKT is activated in ibrutinib resistance BTK Sensistive Resistant BTKC481S Sensitive Relapse Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 Induction of pG1 by CDK4 inhibition reprograms MCL cells for killing by ibrutinib via inhibition of BTK and AKT Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 pG1 inhibits NF-kB activation in BCR signaling Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 Overriding ibrutinib resistance by cell cycle reprogramming • Integrative WES/WTS identified a BTK481S mutation at relapse from ibrutinib after a durable response in MCL • BTK481S mutation is absent in transient ibrutinib response or primary resistance, suggesting addition mechanisms for resistance. • BTK and AKT are concurrently activated in ibrutinib resistance. • Ibrutinib inactivates BTK in MCL cells of resistant patients. • Enhanced proliferation of MCL cells at relapse • pG1 sensitizes resistant MCL cells to Ibrutinib killing via cooperative inactivate BTK and AKT, and inactivation of NF-kB. Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 pG1 reprogramming of MCL cells for PI3K inhibition regardless of C481S BTK mutation Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 pG1 reprograms MCL cells for PI3K inhibitor killing PI3Kd inhibitor GS-1101 (idelalisib) D. Chiron, M. Di Liberto, et al, Cell Cycle, 2013 Induction of pG1 sustains the inactivation of AKT by PI3Kd inhibitor in MCL cells D. Chiron, M. Di Liberto, et al, Cell Cycle, 2013 pG1 reprogramming for PI3K inhibition eradicates ibrutinib-resistant lymphoma cells independent of BTK mutation Cell death Live cells Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014 pG1 reprogramming of MCL cells for PI3K inhibition independent of C481S BTK mutation in MCL Future Directions• Mechanism of pG1 sensitization Cancer metabolism • Mechanism-based combination therapy for MCL Targeting CDK4 with PD 0332991(palbociclib) in combination with ibrutinib Targeting CDK4 in combination with PI3K inhibitor • Mechanism of resistance • Identification of biomarkers via longitudinal integrative WES/WTS and targeted sequencing The Team Maurizio Di Liberto Xiangao Huang David Chiron David Jayabalan Selina Chen-Kiang John Leonard Peter Martin Adriana Rossi Ruben Niesvizky Tomer Mark Lewis Cantley Chris Mason Olivier Elemento Jihye Paik Scott Ely Steve Gross Tim McGraw Jeff Sharman Patients NIH/NCI V Foundation Lymphoma Research Foundation Leukemia and Lymphoma Society Starr Cancer Consortium
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