Declaration of conflict of interest

Transcription

1 Declaration of conflict of interest

2 State of the Art: Addressing Cardiotoxicity Thomas Force, M.D. Center for Translational Medicine Cardiology Division Temple University School of Medicine Philadelphia

3 Outline 1. Brief intro on kinase inhibitors (KIs) and cancer. 2. Why can they cause cardiotoxicity? 3. How should it be addressed?

4 Dysregulation of tyrosine kinases in cancer: Bcr-Abl, the Philadelphia chromosome, CML and ALL Bcr Bcr Oligomerization domain Abl P P Abl Kinase domain Kinase domain Abl Bcr ATP P Substrates Signaling pathways (Ras/ERK; PI3-K) Transformation (cancer)

5 Bcr-Abl and imatinib (Gleevec) Bcr Bcr Oligomerization domain Abl P P Abl Kinase domain Kinase domain Abl imatinib ATP Bcr Substrates P Signaling pathways (Ras/ERK; PI3-K) Transformation (cancer)

6 Table 1. TKIs and mabs in Cancer Agent Class TK target(s) Malignancies Cardiotoxicity/ (Rate)/Other imatinib (Gleevec) dasatinib (Sprycel) Nilotinib (Tasigna) sunitinib (Sutent) Lapatinib (Tykerb) sorafenib (Nexavar) gefitinib (Iressa) erlotinib (Tarceva) Temsirolimus (Torisel) trastuzumab (Herceptin) bevacizumab (Avastin) cetuximab (Erbitux) Panitumumab (Vectibix) Rituximab (Rituxan) alemtuzumab (Campath) TKI ABL1/2, PDGFRa/b, KIT CML, Ph + B-ALL, CMML, HES, GIST Y / (low)* TKI ABL1/2, PDGFRa/b, KIT, SRC family CML Y / (low to mod)* / QT prolongation TKI ABL1/2, PDGFRa/b, KIT CML Unknown TKI VEGFR1/2/3, KIT, PDGFRa/b, RET, CSF-1R, FLT3 RCC, GIST TKI EGFR (ErbB1), HER2 (ErbB2) HER2 + breast cancer N TKI c-/b-raf, VEGFR2/3, PDGFRa/b, KIT, FLT3 RCC, melanoma TKI EGFR (ErbB1) NSCLC N * TKI EGFR (ErbB1) NSCLC, pancreatic cancer, N * novel mtor (indirect- binds to FKBP12 and complex inhibits mtor) RCC N * mab HER2 (ErbB2) HER2 + breast cancer Y / ( Y / (mod) / hypertension, hypothyroidism Y / (low?)* / ACS / hypertension mab VEGF-A Colorectal cancer, NSCLC Y / (low to mod)* / arterial thrombosis mab EGFR (ErbB1) Colorectal cancer, squamous cell carcinoma of head/neck mab EGFR (ErbB1) Colorectal N * mab CD20 B cell lymphoma Unknown mab CD52 B-cell CLL; Y (in patients with mycosis fungoides/sezary syndrome) lestaurtinib TKI JAK2/FLT3 Unknown pazopanib TKI Multi-targeted RCC Unknown vandetanib TKI VEGFR/EGFR NSCLC Unknown cediranib TKI VEGFR NSCLC Unknown alvocidib TKI CDK CLL Unknown enzastaurin KI PKCb B-cell lymphoma Unknown mab, humanized monoclonal antibody; TKI, tyrosine kinase inhibitor; * effect on LV function has not been determined and therefore these represent best. Adapted from Lal et al. JACC 2012 N *

7 The TKI market: Kinase inhibitor patents: ~ 10,000 compounds currently in development

8 The kinome: 500+ kinases 150 propsed to be likely targets in cancer with several to many of these with likely key roles in the heart.

9 Is cardiotoxicity inevitable? Yes On-target toxicity

10 The intersection of genetic and chemical genomic screens identifies GSK-3a as a target in human AML Banerji et al. JCI 2012

11 GSK-3a KO and MI: Deletion leads to increased mortality post-mi due to increased rupture Post MI Survival:GSK3 alpha KO Percent survival p= (WT-MI VS KO-MI) Sham-WT (n=8) Sham-KO (n=7) MI-W T (n=33) MI-KO (n=33) Days Post MI Of concern, the majority of CA patients have CV co-morbidities Lal et al. Circulation 2011

12 Fibrosis (%) Col-1/rRNA MI Sham Deletion of GSK-3a exaggerates cardiac fibrosis and extracellular matrix remodeling post-mi in the remote myocardium WT KO P<0.001 P<0.01 P<0.01 N=3 N=3 N=4 N=4 N=5 N=5 N=7 N=6

13 Targeting the PI3-Kinase pathway in cancer: The need for multiple targets in solid tumors Growth Factors RTKs (EGFR, HER2, c-kit, PDGFRs, Met, etc) Wortmannin LY PI3K (P110α) PTEN PDK1 AKT mtorc2 GSK3 Ras-Raf-ERK-RSK LKB AMPK AMP HIF1α TSC1/2 mtorc1? Rapamycin Energy stress S6K 4E-BP Cheng and Force, Circ Res: 2010 Translation & Cell growth

14 Dealing with on-target toxicity: Bio-markers and imaging Prophylactic therapies D. Cardinale and M. Scherrer-Crosbie

15 Off-target toxicity: Selectivity as the key issue ATP Kothe et al. Biochemistry 2007

16 Type I inhibitors ATP Thus it is relatively easy to make an ATP competitive inhibitor

17 But the high conservation creates a key problem with these agents: lack of selectivity and off-target effects The kinome:

18 Inherent non-selectivity of TKIs- Drugs targeting Abl DDR1 Imatinib Dasatinib Bosutinib Non-kinase targets also identified including NQO2 Bantscheff et al. Nat. Biotech. 2007

19 Double-Edged Sword of the New Cancer Therapeutics Comment on Montani et al. Pulmonary arterial hypertension in patients treated by dasatinib Circulation 2012

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21 Change in LVEF from baseline in patients treated with sunitinib 20% 15% 10% 5% 0% LVEF Change (EF%) from Baseline -5% -10% -15% -20% -25% -30% -35% -40% -45% -50% -55% Patients (n=36) CHF requiring hospitalization, and/or EF drop > 15EF% in 19% of pts. Chu et al. Lancet:2007

22 What is/are the target(s), inhibition of which leads to toxicity: VEGFRs, PDGFRs, AMPK, other?

23 Types of TKIs-designing more selective agents Type I Type III DFG out (Type II) Type I target active conformation, DFG-in: erlotinib, dasatinib, sunitinib Type II target inactive conformation, DGF-out: imatinib, sorafenib, vatalinib Type III employ binding sites and mechs of regulation that are unique to a specific kinase (PD and UO comounds targeting ERKs.

24 Dealing with the inevitable KI market exploding Major financial incentives Less selectivity = used in many cancers Regulatory agencies promoting fast track

25 Why is pre-clinical detection of cardiotoxicity so bad? Don t know enough about the kinases roles in the heart.

26 Force and Kolaja, Nat Rev Drug Disc: 2011

27 Kinase targets in cancer Inhibition definitely or likely bad Kinases VEGFRs PDGFRs Raf-1 / B-Raf PI3-Ka / PDK1 / Akt / Pim / SGK /GSK-3 ERKs LKB1/ CamKK / AMPK CDKs Aurora kinases PLKs Her2 c-kit Jak2 FAK DMPK LTK PKG Inhibition may be good ROCK1/2 PKG CaMKII GRK2 Ask1 LTK CDK4/6 DMPK PKCa PKC Non-kinases PTEN HSPs Adapted from: Force and Kolaja: Nat Rev Drug Disc 2011

28 Sunitinib-induces apoptosis in mice in vivo, but only in the setting of hypertension: No co-morbidities in rodents Chu et al. Lancet:2007

29 Mitochondrial damage in sunitinib-treated mice: Normal LV function Control Sunitinib Chu et al. Lancet:2007

30 Kerkela et al. Clin Trans Sci:2009 Mitochondrial damage in sunitinib-treated patient: IABP placed

31 What do we need (Part 1)? Better pre-clinical models

32 Sorafenib induces cardiomycyte loss in zebrafish TG: cmlc2::dsred-nuc 4dpf fish hearts (20x) N=16 Cheng et al. Circ Res, 2011

33 Fish survival rate at 5dpf, treated at 2dpf EM3 medium Survival % DMSO 0.5 um 1.0 um 2.0 um 5.0 um 0.5 um 1.0 um 2.0 um 5.0 um 0.5 um 1.0 um 2.0 um 5.0 um [Sorafenib] [Sunitinib] [Gefitinib] Medium/DMSO 5uM Sorafenib 5uM Gefitinib 5uM Sunitinib

34 Tabel 1: Videomicroscopic measurements at 5dpf in embryos that were treated at 2dpf with vehicle or 0.5uM TKIs.. n Long-axis Short-axis vehicle ±1.8 EDD ESD FS=(EDD- ESD)/EDD 40.7 ± ±0.03 Wall thickness 40.4 ±1.0 EDD ESD FS=(EDD- ESD)/EDD 62.4 ± ± ±0.04 gefitinib ± ± ± ± ± ± ±0.03 sorafenib ± ±6.4 * 0.33 ±0.03 * 27.1 ±2.2 * 61.3 ± ±2.8 * 0.39 ±0.02 * sunitinib ±4.1 * # 78.6 ±4.5 * 0.23 ±0.03 * 23.9 ±1.0 * 60.8 ± ±2.1 * 0.30 ±0.03 * # * denotes sorafenib or sunitinib vs vehicle or gefitinib; # denotes sunitinib vs sorafenib Cheng et al. Circ Res, 2011

35 What do we need (Part 2)? Biomarkers TnI /TnT: Validated in setting of anthracycline use and suggestive data for trastuzumab (Daniella Cardinale) BNP PET imaging Metabolomics

36 Gerszten and co-workers

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38 What do we need (Part 3)? A full selectivity profile of all new agents (currently ~ 250 kinases) Greater selectivity of agents A better understanding of function of kinases in the heart Increased use of KI re-design strategies a. Avoid bystanders with no/little role in cancer b. Dial down inhibition of kinases mediating toxicity (if not central to tumor progression)

39 What do we need (Part 4)? Full and complete co-operation between cardiology, oncology, toxicology, funding agencies, industry, and non-profits?

40 Human diseases caused by mutations in protein kinases: the other side of the coin

41 Jefferson Medical College Risto Kerkela Adam Dicker Gabor Kari Ulrich Rodek Ron Vagnozzi Hui Cheng MD Anderson JB Durand Aarif Khakoo Dan Lenihan Ed Yeh Acknowledgments CHB; DFCI; BWH Ming Hui Chen Tammy Chu Roche Kyle Kolaja