Pushing the boundaries-targeted therapies

Transcription

1 Pushing the boundaries-targeted therapies Professor Grant McArthur MB BS PhD Director Melanoma and Skin Cancer VCCC Parkville, Peter MacCallum Cancer Centre Lorenzo Galli Chair of Melanoma & Skin Cancers, The University of Melbourne

2 Disclosure Information - I have the following financial relationships to disclose - Research support from: Pfizer, Celgene & Ventana - Consultant: Provectus

3 Melanoma an Immunogenic Oncogene-driven Cancer. McArthur & Ribas, J Clinical Oncology, 2013

4 Melanoma an Immunogenic Oncogene-driven Cancer. McArthur & Ribas, J Clinical Oncology, 2013

5 Novel Targets in Melanoma Activating p53 RAS/RAF/ERK Pathway Cell Cycle Targets? X Hanahan and Weinberg, 2000?

6 Novel Targets in Melanoma Activating p53 RAS/RAF/ERK Pathway BH3-mimetics BCL2-Venetoclax BCL2-BCXL- Navitoclax/Obatoclax MCL1i Cell Cycle Targets? X Hanahan and Weinberg, 2000?

7 Novel Targets in Melanoma Metabolic Targets? ± Hanahan and Weinberg, 2011

8 Novel Targets in Melanoma Cell Cycle Targets Hanahan and Weinberg, 2000

9 Cell Cycle Targets in Melanoma Xu & McArthur, Current Oncology Reports, 2016

10 Melanoma The Cancer Genome Atlas Cutaneous melanomas Non-glabrous skin Mainly regional metastases NRAS mut (28%) BRAF mut (52%) NF1 mut (14%) MITF amp (4%) BRAF amp (12%) MDM2 amp(12%) NOTCH2 amp (5%) KIT amp (3%) KIT mut (3%) PDGFRα amp (3%) PDGFRα mut (10%) CCND1 amp (4%) TERT amp (5%) PPP6C mut (7%) TP53 mut (7%) PTEN mut (8%) PTEN del (12%) CDKN2A mut (13%) CDKN2A del(40%) NRAS G12/G13/Q61 50 BRAF V600 CDK Cancer Genome Atlas Research Network, Ian R. Watson, Lihua Zou, Chang-Jiun Wu, TCGA Workshop, 2012 ASCO 2014: Michael A. Davies, MD, PhD

11 PFS Probability OS Probability COMBI-d: CDKN2A Loss in the Dabrafenib + Trametinib Arm PFS CDKN2A WT (n = 45) OS CDKN2A WT (n = 45) CDKN2A mutation and deletion were significantly associated with poorer OS (P = a ) and PFS (P < a ) y PFS, 27% y OS, 55% Preclinical data suggest that combination with CDK4/6 inhibitors could be a beneficial strategy 3-y OS, 24% y PFS, 6% CDKN2A Mut (n = 18) 0.0 CDKN2A Mut (n = 18) Number at risk Months From Randomization WT Mut a Cox proportional hazards P value; +, censored. Number at risk Months From Randomization WT Mut Presented by: Keith T. Flaherty, MD

12 Novel Targets in Melanoma RAS/RAF/ERK Pathway Cell Cycle Targets Hanahan and Weinberg, 2000

13 NRAS, BRAF and CDK4 NRAS Q61X BRAF V600E RAS CycD1 P MEK RAS-less prb P ERK CDKN2A Adapted from Drosten Barbacid, EMBO J, 2010 CycD1 CDK4 prb G 1 -S Progression

14 Cyclin D1 % stained NUC NRAS, BRAF and CDK4 NRAS Q61X BRAF V600E 100 Cyclin D1 P P MEK ERK CDKN2A 20 CycD1 CDK4 prb 0 Baseline Day 15 PD Vemurafenib PLX06-02 study G 1 -S Progression McArthur et al ASCO, 2011; Trunzer et al, JCO, 2013

15 C054 SK-MEL24 SK-MEL3 MALME-3M HS294T C088 G361 C052 MEL-HO SK-MEL5 A15 C002 D35 C057 C001 D36 RVH-421 WM115 COLO-800 C027 D08 HT144 C062 D05 C074 D17 C021 SK-MEL28 A375 CHL1 LOX-IMVI C32 D04 WM266-4 A11 C055 C089 C044 MeWo A02 D14 D41 D20 A2058 C071 C013 D24 PD991 GI50(nM) Activation of the CDK 4 Pathway Correlates with Palbociclib Sensitivity Resistant Wild Type Mutant BRAF NRAS WT V600E V600E V600E V600E V600K V600E WT V600E V600E V600K WT WT V600E WT V600E V600E V600D V600E WT WT V600E V600E V600E V600E V600E WT V600E V600E WT V600E V600E WT V600D WT V600E V600E V600E WT V600E V600E V600E V600E V600E V600E WT WT Q61K WT WT WT WT WT WT WT WT WT WT Q61K WT WT Q61K WT WT WT WT Q61L Q61L WT WT WT WT WT WT WT WT WT WT WT Q61L WT WT WT WT WT WT WT WT WT WT WT WT Q61L WT p16ink4a Dele Dele NO Dele Dele NO Dele Mut Dele Dele Met Dele Mut NO Mut Dele Dele Dele NO Dele Dele Dele Mut Dele Met NO WT ted ted Prot ted ted Prot ted ated ted ted hylat ted ated Prot ated ted ted ted Prot ted ted ted ated ted hylat Prot CDK4 (R24C) CDK4 (R24C) WT Mut Mut Dele Mut Dele Dele Dele Dele Dele Mut Mut Dele Dele WT WT WT WT WT WT ated ated ted ated ted ted ted ted ted ated ated ted ted Young et al, PCMR, 2014

16 NRAS, BRAF and CDK4 NRAS Q61X BRAF V600E BRAFi P P MEK ERK CDKN2A CycD1 CDK4 CDK4i prb G 1 -S Progression

17 BRAF and CDK4 NRAS Q61X BRAF V600E P P MEK ERK CDKN2A CycD1 CDK4 prb FOXM1 G 1 -S Progression Suppression Senescence Mitosis DNA-damage response Sheppard & Kirby, unpublished

18 Targeting prb and p53 in melanoma? NRAS Q61X BRAF V600E BRAFi CDK2i P P MEK ERK CDKN2A RNA Pol 1i p53 CycE p21 CDK2 CycD1 CDK4 CDK4i MDM2 prb MDM2i G 1 -S Progression

19 Novel Targets in Melanoma Activating p53 HDM2i AMG232 DS-3032 RO RO HDM201 RNA Pol 1i CX-5461 Hanahan and Weinberg, 2000

20 CX-5461, orally available, small molecule that selectively targets the Pol I transcription initiation factor complex SL-1 Drygin et al, Can Res, 2011

21 Novel Targets in Melanoma Metabolic Targets Hanahan and Weinberg, 2011

22 Metabolic Targets in Melanoma BRAF Inhibition Smith, Rao & McArthur, Pharmacological Research, 2016

23 Could inhibition of glucose metabolism be a driver of response? Baseline Day 15 Kim, MD Anderson

24 Genome-wide Vemurafenib Enhancement Screen siotp Dharmacon Human sigenome SmartPool Library WM266.4 BRAF V600 Melanoma cells Forward transfection DMSO Vemurafenib (300nM; IC20) Measure Glycolysis & Cell Viability Viability DAPI Cell Count Glycolysis Lactate Production per Cell DAPI p53 Composite Lactate Tiffany Parmenter, Lorey Smith

25 Preventing the metabolic/biosynthetic switch. Lorey Smith

26 Melanoma an Immunogenic Oncogene-driven Cancer. McArthur & Ribas, J Clinical Oncology, 2013

27 Acknowledgements Shatha AbuHammad Karen Sheppard Carleen Cullinane Claire Martin Nicole Haynes Laura Kirby Allen Foo Richard Young Kelly Waldeck Stephen Fox Lorey Smith Tiffany Parmenter Aparna Rao Gretchen Poortinga Ross Hannan Rick Pearson John Lim Denis Drygin

28 SAVE THE DATE! October 2017 Brisbane Australia