Antireplication Agents: CDK Inhibitors and Telomerase Inhibitors Richard S. Finn, MD Assistant Professor of Medicine Geffen School of Medicine at UCLA
Dec 26, 2015
Antireplication Agents: CDK Inhibitors and Telomerase Inhibitors
Richard S. Finn, MD
Assistant Professor of Medicine
Geffen School of Medicine at UCLA
Faculty Disclosure
Richard Finn, MD, has disclosed that he has received fees for non-CME services from Genentech.
Cyclin D Kinases and Cancer
CDKs are a subgroup of seine/ threonine kinases In general very small proteins (34-40 kDa) Bind to activating proteins: cyclins Without cyclins, CDKs have little kinase activity
Play a key role in regulating cell cycle progression through all phases of the cell cycle Various cyclin/ CDK complexes act at different parts of the cell cycle Temporal and quantitative regulation
Negative regulation by cyclin dependent kinase inhibitors (CKI) INK 4 family (p15, p16, 18, p19 Cip/ Kip family (p21, p27, p57)
Alterations in CDKs are uncommon, compared with cyclin dysregulation Altered regulation/ expression in many malignaices
Cyclin D1 amplification has been described in various malignancies, including breast cancer, with variable prognostic significance t(11;14) mantle cell lymphoma
Rb loss, a well known oncogenic event
1. Finn RS, et al. Breast Cancer Res. 2009;11:R77. 2. Lundberg AS, et al Eur J Cancer. 1999;35:1886-1894.3. Buckley MF, et al. Oncogene. 1993;8:2127-2133. 4. Dickson C, et al. Cancer Lett. 1995;90:43-50.
Cyclin D Kinases and Cancer
Vermullen Cell Proliferation
Modified from Figure 8.19 . The Biology of Cancer. © Garland Science 2007.
p16(INK4a)
Rb as Master-Regulator of the R Point
CDK/ Cyclin Inhibitors Targeting CDK
>50 inhibitors described Generally in several classes
– Purine analogoues (ie roscovitine) Selicicilib (CYC202) CDK2/E CDk 2/A CDK7 CDK 9
– Pyrimidine analgoues Dinaciclib (SCH727965) CDK 2, CDk5, CDK 1, CDK 9
– Flavonoids (flavopiridol)– Indolinones– Staurosporine
Targeting Cyclin cyclin expression modulators (ON013105)
CDK/ Cyclin Inhibitors Selicicilib (CYC202)
– Phase II Nasopharyngeal APPRAISE Study
Randomized Phase II, NSCLCA 3rd line or greater vs BSC
Dinaciclib (SCH727965) Phase II
– Melanoma– AML
ON013105 Phase I- mantle cell lymphoma
PD 0332991: Background
The compound
Potent, selective, reversible inhibitor of CDK4,6
Small molecule
Oral agent
The opportunity
Potential first in class
Potential impact on hematopoietic and solid tumors
Potential use in pediatric indications
Single-agent and combination approaches under investigation
NN O
N
NH
O
N
N
NH2
+
SO
OO
OH
PD 332991
Finn RS, et al. Breast Cancer Res. 2009;11:R77.
Inactivates Rb andallows progression
Target of PD 0332991
p16(INK4a)
Rb as Master-Regulator of the R Point
Modified from Figure 8.19 . The Biology of Cancer. © Garland Science 2007.
Sorlie et al PNAS 2001
Human Breast Cancer Cell Line Panel Can Recapitulate the Molecular Heterogeneity of Clinical Disease
51 HumanBreast Cell Lines
25 Luminal
26 Non-luminal
13 Basal/Progenitor
9 Mesenchyma
l
4 Non-malignant
10 ER positive
Normal HER-2
9 ER positive
HER-2 amplified
6 ER negative
HER-2 amplified
1 HER-2 Amplified
1 HER-2 Amplified
0
100
200
300
400
500
600
700
800
900
1000
Subtype Luminal Non-luminal/post EMT
HER2 Amplified Non-luminal Immortalized
PD-0332991: CDK 4/6 Inhibitor: Breast PanelIC
50 n
M
Finn RS Breast Can Res 2009
HCC 1419
0
10
20
30
40
50
60
70
80
90
100
G0/G1 S G2
EFM192A
0
10
20
30
40
50
60
70
80
90
100
G0/G1 S G2
MCF7
0
10
20
30
40
50
60
70
80
90
100
G0/G1 S G2
HCC 1937
0
10
20
30
40
50
60
70
80
90
100
G0/G1 S G2
MDA MB 468
0
10
20
30
40
50
60
70
80
90
100
G0/G1 S G2
HCC 1187
0
10
20
30
40
50
60
70
80
90
100
G0/G1 S G2
%
%
PD 0332991: Cell Cycle Analysis
Sensitive lines
Resistant linesFinn RS, et al. Breast Cancer Res. 2009;11:R77.
MB453
T47D
EFM19
HCC1187
HCC1954
CAL 51
A. Total pRb
Sensitive
Resistant
B. Phospho-Rb (serine 780)
MCF7
0 30’ 60’ 12 hr 24 hr 48 hr 12 hr30’ 48 hr60’ 24 hr0Time
Finn RS, et al. Breast Cancer Res. 2009;11:R77.
PD 0332991: Effects on Phosphorylation on Retinoblasoma Gene Product
Hypothesis: Patient Selection in Breast Cancer Population
ElevatedCyclin D1RB
Decreasedp16
Gauthier ML, et al. Cancer Cell. 2007;12:479-491.
MCF7
0
20
40
60
80
100
10000 5000 2500 1250 625 312
100 50 25 12.5 6.25 3.125
Concentration (nM)
% In
hib
itio
n
Tam
PD
0
20
40
60
80
100
5000 2500 1250 625 312
50 25 12.5 6.25 3.125Concentration (nM)
% In
hib
itio
n
Tam
PD
EFM19
T47D
Tam
PD
0
20
40
60
80
100
5000 2500 1250 625 312
50 25 12.5 6.25 3.125Concentration (nM)
% I
nhib
itio
n
0
1
2
5000 2500 1250 625 312
50 25 12.5 6.25 3.125
Concentration (nM)
CI
Tam
PD
0
1
2
5000 2500 1250 625 312
50 25 12.5 6.25 3.125
Concentration (nM)
CI
Tam
PD
0
1
2
1000 5000 2500 1250 625 312.5
100 50 25 12.5 6.25 3.125
Concentration (nM)
CI
Combo
PD-2991
Tamoxifen
TRIO 18/A5481003: Phase I/II Study of Letrozole in Combinations With PD-0332991 in Postmenopausal ER+ Advanced Breast Cancer
Phase I complete
Randomized phase II accruing
ClincailTrials.gov. NCT00721409.
TRIO 18: Phase I Patient Summary
Slamon DJ, et al. ASCO 2010. Abstract 3060.
TRIO 18: Most Common AEs (N = 12)
PT, n Grade 1 Grade 2 Grade 3 Grade 4 Total
Neutropenia 0 1 7 2 10
Fatigue 6 2 0 0 8
Leukopenia 0 3 2 1 6
Nausea 5 0 0 0 5
Diarrhea 4 0 0 0 4
Anemia 2 1 0 0 3
Cough 2 1 0 0 3
Decreased appetite 3 0 0 0 3
Dyspnea 3 0 0 0 3
Hot flush 2 1 0 0 3
Nasal congestion 2 1 0 0 3
Arthralgia 1 1 0 0 2
Back pain 2 0 0 0 2
Creatinine increased 0 1 1 0 2
Slamon DJ, et al. ASCO 2010. Abstract 3060.
TRIO 18: Most Common Treatment-Related AEs (N = 12)
PT, n Grade 1 Grade 2 Grade 3 Grade 4 Total
Neutropenia 0 1 7 2 10
Fatigue 4 2 0 0 6
Leukopenia 0 3 2 1 6
Nausea 5 0 0 0 5
Anemia 2 1 0 0 3
Decreased appetite 3 0 0 0 3
Diarrhea 3 0 0 0 3
Hot flush 2 1 0 0 3
Dyspnea 2 0 0 0 2
Headache 1 1 0 0 2
Thrombocytopenia 1 1 0 0 2
Slamon DJ, et al. ASCO 2010. Abstract 3060.
TRIO 18: Phase I Summary
Phase I (N = 12)
• MTD: PD 0332991 125 mg QD (schedule 3/1) in combination with letrozole 2.5 mg QD
• 3 DLTs: – 2 patients with grade 4 neutropenia– 1 patient with 5 doses held due to elevated creatinine deemed treatment related
• No treatment-related SAEs
• No discontinuations due to AEs
– Common treatment-related AEs: neutropenia, leukopenia, fatigue
• No febrile neutropenia
• No drug-drug interaction
• Efficacy: 3 PRs and 9 SDs (PR: 33%; CBR: 67%)
• Median duration of treatment: 12 mos (range: 2-21+)
• Currently 6 patients activeSlamon DJ, et al. ASCO 2010. Abstract 3060.
Hypothesis: Biomarkers Predictive of PD 0332991 SensitivityDesired biomarker profile:
ER+, HER2-– Wild-type Rb1– Plus
• Amplified cyclin D1/CCND1
OR • Inactivated CDKN2A/p16INK4a
Finn RS, et al. Breast Cancer Res. 2009;11:R77.
Phase II Study Design (Part I, Completed)
ER+, HER2- breast cancer
Stratification Factors: Disease site
− Visceral vs bone only vs other
Disease-free interval− > 12 vs ≤ 12 mos
ER+, HER2- breast cancer
Stratification Factors: Disease site
− Visceral vs bone only vs other
Disease-free interval− > 12 vs ≤ 12 mos
RRAANNDDOOMMIIZZAATTIIOONN
RRAANNDDOOMMIIZZAATTIIOONN
Arm APD 0332991 125 mg/day
(Schedule 3/1)
+ Letrozole 2.5 mg/day
Arm APD 0332991 125 mg/day
(Schedule 3/1)
+ Letrozole 2.5 mg/day
Arm BLetrozole 2.5 mg/day
Arm BLetrozole 2.5 mg/day
N = 60
1:1
Primary endpoint: PFS
ClincailTrials.gov. NCT00721409.
Phase II Study Design (Part II, Ongoing)
ER+, HER2- breast cancer
Biomarker Selection
CCND1 amp
And/or loss of p16
ER+, HER2- breast cancer
Biomarker Selection
CCND1 amp
And/or loss of p16
RRAANNDDOOMMIIZZAATTIIOONN
RRAANNDDOOMMIIZZAATTIIOONN
Arm APD 0332991 125 mg/day
(Schedule 3/1)
+ Letrozole 2.5 mg/day
Arm APD 0332991 125 mg/day
(Schedule 3/1)
+ Letrozole 2.5 mg/day
Arm BLetrozole 2.5 mg/day
Arm BLetrozole 2.5 mg/day
N = 150
1:1
Primary endpoint: PFS
ClincailTrials.gov. NCT00721409.
Similar Observations in Other Histologies
Ovarian cancer[1]
Glioblastoma[2,3]
Multiple myeloma[4]
1. Konecny GE, et al. Clin Cancer Res. 2011;17:1591-1602. 2. Michaud K. Cancer Res. 2010;70:3228-3238. 3. Wiedemeyer WR, et al. Proc Natl Acad Sci U S A. 2010;107:11501-11506. 4. Menu E, et al. Cancer Res. 2008;68:5519-5523.
Telomerase and Cancer
Telomerase: reverse transcriptase that adds DNA repeats (TTAGGG) to the 3’ end of DNA strands (telomere region)– Consists of 2 molecules each of telomerase reverse transcriptase
(TERT), telomerase RNA (TERC), and dyskerin (DKC1)
Protects DNA from genomic damage/loss during replication
In cancer, cells that lose telomeres become unstable, accumulate genetic damage, and eventually undergo apoptosis
Activation of telomerase can prevent the apoptosis event and cause cells to become immortalized– Telomerase is activated in 90% of cancer (but not somatic cells)
Hypotheses: block telomerase, induce telomere shortening, genetic instability and cell death
Shay JW, et al. Human Mol Gen. 2001;10:677-685.
Telomerase MOA
Harley Nat rev Cancer 2008
Telomerase and Cancer
Various potential methods of silencing telomerase– Oligonucleotides
• Target the template region (activation site) of telomerase• Imetelstat (GRN163L): 13 mer oligonucleotide, not antisense but a direct
telomerase inhibitor[1]
– Vaccines• Dendritic cell–based (GRNVAC1)
• Use hTERT pulsed autologous dendritic cells• Phase I: generally well tolerated, achieved levels felt to be sufficient for
hTERT inactivation[2]
• Phase II study in AML as consolidation
• Nondendritic based • Phase I in solid tumors (V934/V935)[4]
• GV1001 peptide with temozolomide for melanoma[5]
1. Herbert BS, et al. Oncogene. 2005;24:5262-5268. 2. Su Z, et al. J Immunol. 2005;174:3798-3807. 3. ClinicalTrials.gov. NCT00510133. 4. ClinicalTrials.gov. NCT00753415. 5. ClinicalTrials.gov. NCT01247623.
Conclusions
Newer targets in molecular oncology include the CDK pathway and telomerase
Ongoing clinical studies (TRIO18) with PD 0332991, an oral, small molecule kinase inhibitor, in breast cancer aim at validating laboratory science that identified ER+ breast cancer as being susceptible to CDK 4/6 inhibition To date, predictable and manageable toxicity has been seen with this
class of agent
Studies with other CDK targeted agents and Cyclin targeted agents are ongoing MCL should be “proof of concept”
Telomerase inhibitors are moving to the clinic and hold promise but predictors of response will be necessary for successful clinical development Including vaccine strategies and short-oligos