Download - Targeting the Cell Cycle in Lymphoma Therapy Selina Chen- Kiang Weill Cornell Medical College
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Targeting the Cell Cycle in Lymphoma Therapy
Selina Chen-KiangWeill Cornell Medical College
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CDK Inhibitors
Non-Selective CDK4/CDK6 inhibitorsTargeting 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 3Melanoma
• LY2835219Non-Small Cell Lung CarcinomaBreast Cancer
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The Cell Cycle
G1S
G2
M
p21p27p57
Negative Go
Positive
Cyclin D + CDK4/6
pS-Rb-E2F
Cyclin E + CDK2
pST-Rb E2F release
p16p15p18p19
CDK: Cyclin-Dependent Kinasep18INK4c (CDKN2C)
mid-G1 checkpoint
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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 TherBaughn et al., 2006, Cancer ResearchMenu et al., 2008, Cancer Research
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Targeting CDK4/CDK6 in combination therapy
Partner agent (low dose, selective )
CDK4/6 Inhibitor
Weill-Cornell
Mantle cell lymphoma Phase I single agent Multiple Myeloma Phase I/II PD-bortezomib-Dex Mantle cell lymphoma Phase I PD 0332991-bortezomib
2014Mantle cell lymphoma Phase I PD 0332991-Ibrutinib Multiple myeloma Phase I PD 0332991-Lenalidomide-Dex
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Cyclin D + CDK4/6
PD 0332991
G1
S
G2
M
Go
pS-Rb
Prolonged early G1 arrest (pG1) Hypothesis
Prolonged inhibition of CDK4/6
Prolonged early G1 arrest (pG1)Expression of only genes programmed for early G1
Sensitizing tumor cells to cytotoxic killing
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Release of prolonged early G1 block
Cell cycle synchronization incomplete restoration of scheduled gene expression
Further sensitizing tumor cells to cytotoxic killing
Cyclin D + CDK4/6 PD 0332991Reversible
G1
S
G2
M
Go
pS-Rb
pG1 Hypothesis
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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
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Phase I study of PD 0332991 + bortezomib in patients with recurrent MCL
Biopsy ★ ★ ★pG1 pG1-S
Martin, Di Liberto, Leonard, et al, unpublished
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Phase I study of PD 0332991 + bortezomib in patients with recurrent MCL
% change in tumor size (by patient)
Martin, Leonard, unpublished
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M. Di Liberto, D. Chiron, C. Mason, P. Martin, J. Leonard, S. Ely, 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?
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Cyclin D + CDK4/6
PD 0332991
G1
S
G2
M
Go
pS-Rb
Prolonged early G1 arrest (pG1) Hypothesis
Prolonged inhibition of CDK4/6
Prolonged early G1 arrest (pG1)Expression of only genes programmed for early G1
Sensitizing tumor cells to cytotoxic killing
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Longitudinal Integrative analysis of whole exome-sequencing (WES) and whole transcriptome-sequencing (WTS) of serial biopsies, using cheek swab as a control.
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Integrative WES and WTS analysis
CD5+CD19+ isolation
WTS (100-100ng RNA)
mRNA abundance
Alternative splicingSNV
s
Lymph node biopsy
WES (50ng DNA)
CNV
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Only 1% of the genes that were repressed in (pG1, day 8) in clinically responding patients (R) were up-regulated in pG1 non-responding patients (NR). Candidate biomarkers for the PD 0332991-bortezomib therapy?
Chiron, Di Liberto, Mason, Martin, et al, unpublished
Differential regulated genes
• Glucose homeostasis• Redox homeostasis• Cell migration
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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 homeostasisRedox homeostasisCell migration
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pG1 reprogramming MCL cells for ibrutinib inhibition of Bruton Tyrosine Kinase (BTK)
Ibrutinib is effective in MCL. However, relapse is frequent andassociated with aggressive proliferation and poor prognosis
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Relapse-specific C481S mutation in BTK in MCL--Longitudinal integrative WES and WTS analysis
Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014
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Relapse-specific C481S mutation in BTK in MCL--Longitudinal integrative WES and WTS analysis
• However, BTKC481S mutation is absent in transient ibrutinib response (< 5months) or primary resistance (6/6)
At least two mechanisms of Ibrutinib relapse -
• BTKC481S mutation is detected in durable ibrutinib response (>14 or 30 months, 2/2.
Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014
BTK C481S mutation undetected before Ibrutinib relapse
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• BTK is inactivated by ibrutinib in MCL cells of both sensitive and resistant patients in vivo• PI3K-AKT is activated in ibrutinib resistance
BTKC481SBTK
Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014
Sensistive Resistant Sensitive Relapse
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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
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pG1 inhibits NF-kB activation in BCR signaling
Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014
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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
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pG1 reprogramming of MCL cells for PI3K inhibition regardless of C481S BTK mutation
Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014
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pG1 reprograms MCL cells for PI3K inhibitor killing
D. Chiron, M. Di Liberto, et al, Cell Cycle, 2013
PI3Kd inhibitorGS-1101(idelalisib)
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Induction of pG1 sustains the inactivation of AKT by PI3Kd inhibitor in MCL cells
D. Chiron, M. Di Liberto, et al, Cell Cycle, 2013
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pG1 reprogramming for PI3K inhibition eradicates ibrutinib-resistant lymphoma cells
independent of BTK mutation
Chiron, Di Liberto, Martin et al, Cancer Discovery, 2014
Cell death
Live cells
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pG1 reprogramming of MCL cells for PI3K inhibition independent of C481S BTK mutation in
MCL
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Future Directions-
• Mechanism of pG1 sensitizationCancer metabolism
• Mechanism-based combination therapy for MCLTargeting CDK4 with PD 0332991(palbociclib) incombination with ibrutinib
Targeting CDK4 in combination with PI3K inhibitor
• Mechanism of resistance
• Identification of biomarkers via longitudinal integrative WES/WTS and targeted sequencing
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Maurizio Di Liberto Xiangao Huang David Chiron David Jayabalan Selina Chen-Kiang
John Leonard Ruben Niesvizky Peter Martin Tomer Mark Adriana Rossi
Lewis Cantley Scott ElyChris Mason Steve GrossOlivier Elemento Tim McGrawJihye Paik Jeff Sharman
Patients
NIH/NCIV FoundationLymphoma Research FoundationLeukemia and Lymphoma SocietyStarr Cancer Consortium
The Team