Novel Targets And Strategies in Glioblastomas Patrick Y. Wen, M.D. - PowerPoint PPT Presentation

Novel Targets And Strategies in Glioblastomas Patrick Y. Wen, M.D. Center For Neuro-Oncology Dana Farber/Brigham and Women ’ s Cancer Center Division of Neuro-Oncology, Department of Neurology Brigham and Women ’ s Hospital g p Harvard Medical School

DISCLOSURES DISCLOSURES • Research Support • Advisory Board R h S t Ad i B d – Amgen – Merck – Astra Zeneca Astra Zeneca – Novartis Novartis – Boehringer Ingelheim – Vascular Biogenic – Esai – NeOnc Inc – Exelixis E li i • Speaker – Genentech/Roche – Merck – Geron – Genentech/Roche Genentech/Roche – Medimmune – Merck – Novartis N ti – Sanofi-Aventis – Vascular Biogenics

Treatment of High Grade Gliomas Treatment of High-Grade Gliomas

Mil Milestones in Neuro ‐ Oncology t i N O l A Approvals l TMZ up front Radiotherapy for GBM TMZ for Avastin for relapsed AA Lomustine accelerated recurrent Gliadel wafer approval GBM Carmustine 1970 1980 1990 2000 2010 First US First US Macdonald commercial CT RANO Brain Tumor commercial criteria: Criteria Clinical Trial MRI MRI + steroids; ; Levin criteria: Levin criteria: Endpoints WHO Pathology CT scans ASCO Workshop Criteria Workshop Technology Advances Technology Advances AA=anaplastic astrocytoma; CT=computed tomography; GBM=glioblastoma multiforme; MRI=magnetic resonance imaging; RANO=Response Assessment in Neuro ‐ Oncology.

VEGF : Aflibercept VEGFR : Axitinib, Brivanib, Cabozantinib, Cediranib, Dasatinib, Foretinib, Lenvatinib, Nintedanib, Pazopanib, Pegdinetanib, Sorafenib, Sunitinib, Vandetanib Ang: CVX 060, Trebananib Tie-2 : Cabozantinib EGF : ABT-806, Cetuximab, FGFR: Brivanib, Lenvatinib, Nintedanib Nimotuzumab, Panitumumab CXCR4 : Plerixafor CXCR4 : Plerixafor HGF : Rilotumumab BLOOD VESSEL IL-2: Basiliximab, Daclizumab ECM PDGF α : IMC-3G3, MEDI-575 PGF: RO5323441 VEGF : Bevacizumab, Ramucirumab Smo Smo Notch Notch N INTEGRIN Cilengitide c-KIT : Axitinib, Vismodegib MK0752 PKC LDE225 RO4929097 Cabozantinib, Imatinib, Enzastaurin PLX3391, Sunitinib, Tandutinib Bosutinib, Src CXCR4: Plerixafor ICN HSP Dasatinib, EGFR : Afatinib, Gli1/2 Nintedanib Dacomitinib, Erlotinib, Client Gefitinib, Lapatinib, Protein Ri d Rindopepimut (EGFRvIII) i t (EGFR III) PTEN PI3K Ras Tipifarnib HGFR/c-Met : Cabozantinib, Onartuzumab HSP PDGFR : Axitinib, Brivanib, Vitespen Raf Crenolinib, Dasatinib, Sorafenib Akt Akt Imatinib, Lenvatinib, Imatinib Lenvatinib Perifosine, P if i Nintedanib, Pazopanib, PX-866 Sorafenib, Sunitinib, Client MEK Tandutinib Protein TGF : LY2157299 Everolimus, Proteosome mTOR Sirolimus, Temsirolimus Temsirolimus ERK XL-765, GDC-0084 Bortezomib AZD8055, CC223 Veliparib PARP Panobinostat, HDAC Alexander, Lee Valproic Acid, Chk DNA Vorinostat et al. 2013 NUCLEUS

• New approaches to trial design Outline • New therapies and targets • Issues

R Reasons for Lack of Progress in Targeted Molecular f L k f P i T t d M l l Therapies in Glioblastomas • Poor models • Blood-brain barrier • Co-activation of tyrosine kinases C i i f i ki • Redundant signaling pathways g g p y • Spatial and temporal heterogeneity • Failure to genetically enrich patient population • Stem cells Stem cells

Bypassing The Blood Brain Barrier Bypassing The Blood Brain Barrier

B Benarroch Neurology 2012;78:1268 h N l 2012 78 1268

Connolly et al, SNO 2012 Slide courtesy of May Han, Aveo

Current Design Current Design Surgery R Recurrent PK PK Tumor PET PET MRI MRI Blood biomarkers Blood biomarkers Therapy Therapy

Convection ‐ Enhanced Delivery Convection ‐ Enhanced Delivery

Low density Lipoprotein Receptor Related Protein (LRP 1) (LRP ‐ 1) TPA Angiopep (tissue plasminogen activator)  2-Macroglobulin • Transports small and large (MW ~ 700 kDa) RAP molecules (> 40 ligands) molecules (> 40 ligands) • One of the most expressed  Thyroglobulin receptor at the surface of the receptor at the surface of the Lactoferrin BBB • Expressed on cancer cells p • Expressed also in liver, lung and Cell Membrane ß ovarian tissues LRP-1: ~600kDa (  515,  85)

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ANG1005 ANG1005 Low density y lipoprotein receptor related protein (LRP1)

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2013; 19(6):1567 ‐ 1576

Science 2011;344:1727

Pulse Dosing

Vivanco et al. Cancer Discovery 2012;2:458 ‐ 71 Vivanco et al. Cancer Discovery 2012;2: 458 ‐ 271 GBM Lung Cancer

Vivanco et al. Cancer Discovery 2012

Vivanco et al. Cancer Discovery 2012

Are we delivering the drugs appropriately? • Continuous dosing versus pulse dosing • Administer targeted drug before or after chemotherapy Ad i i t t t d d b f ft h th NSCLC • – Solit et al CCR 2005;11:1983 – Riely JCO 2009:27;264

Targeted Molecular Therapies Targeted Molecular Therapies The Cancer Genome Atlas Research Network. Nature . 2008;455:1061-1068;

Stum et al. Cancer Cell 2012;22:425 ‐ 437

Failure To Genotype Patients

S equencing Epigenetic Analysis Set of activated Combinations of kinases and appropriate drugs pathways Ivy Foundation Early Phase Clinical Trials Consortium DF/HCC DF/HCC MSKCC UCLA UCSF UCSF MDACC U Utah

New Targets • FGFR/TACC • BRAF • CDK4 CDK4 • PI3K PI3K • WeeI

PI3 Kinase Inhibitors Growth Factors, etc Ras Raf PI3K inhibitor XL765 XL765 XL147 Mek BKM120 PX866 Erk Erk GDC0084 Proliferation Proliferation

BKM120 BKM120 • Oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor belonging to the 2,6-dimorpholino pyrimidine g g , p py derivative family • Inhibits p110 α , p110 β , p110 δ and p110 γ p , p β , p p γ • Cross the blood-brain barrier (brain/blood ratio 2) • Taken orally once daily T k ll d il • Inhibits the growth of U87MG and GBM explants in vivo 39

Ivy Foundation Early Phase Clinical Trials Consortium A Phase II study of BKM120 for patients with recurrent glioblastoma and activated PI3K pathway

BKM 120 T i l BKM 120 Trial Patient Eligibility • Activation of PI3K pathway: • Activation of PI3K pathway: – PIK3CA/PIK3R1 mutation or – PTEN mutation, loss of PET by FISH, or PTEN IHC negative g Goal • 30 PTEN loss • 20 PIK3CA/PIK3R1 mutants 20 PIK3CA/PIK3R1 mutants 44

Next Steps Next Steps • Isoform specific Inhibitors – ? Beta specific isoforms better for PTEN loss ? Beta specific isoforms better for PTEN loss – ? Alpha specific isoforms for PI3Ca mutants • Combinations – BKM120 +RT+TMZ BKM120 +RT+TMZ – BKM120 + LDE225 (SMO inhibitor) – BKM120 + INC 280 (MET inhibitor)

Science 2012

Phase II Trial of BGJ398 (FGFR inhibitor) Phase II Trial of BGJ398 (FGFR inhibitor)

TCGA TCGA The Cancer Genome Atlas Research Network. Nature . 2008;455:1061-1068;

PD-0332991 (CDK 4/6 inhibitor) Michaud et al: Cancer Res 2010;70:3228

Michaud et al: Cancer Res 2010;70:3228 Michaud et al: Cancer Res 2010;70:3228

LY2835219 (CDK4/6 Inhibitor) Sanche Martine et al Sanchez Martinez et al

Sanchez ‐ Martinez et al h i l

BRAF and/or MEK inhibitors for BRAFV600E mutated gliomas? mutated gliomas?

Flaherty et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600E Mutations Melanoma with BRAF V600E Mutations NEJM 2012; 2012 Nov;367(18):1694-703

A Phase II, Open-label Study in Patients with BRAF V 600E Mutated Rare Cancers with Several Histologies to V Mutated Rare Cancers with Several Histologies to Investigate the Clinical Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib Dabrafenib Trametanib

Histologies Histologies • Anaplastic Thyroid Carcinoma • Biliary Tract Cancer • Diffuse Large B Cell Lymphoma • GIST • Hairy Cell Leukemia • High Grade Glioma (GBM, Anaplastic PXA, Anaplastic Hi h G d Gli (GBM A l i PXA A l i ganglioglioma) • Low-Grade Gliomas (PXA Ganglioglioma Pilocytic Low-Grade Gliomas (PXA, Ganglioglioma, Pilocytic Astrocytoma) • Multiple Myeloma p y • NSGCT/NGGCT • Small Intestine Adenocarcinoma

Plummer: Clin Cancer Res 2010;16(18); 4527–31 Plummer: Clin Cancer Res 2010;16(18); 4527 31 Double strand break Single strand break Non- Homologous Homologous homologous homologous end joining Recombinati (NHEJ) on

Plummer: Clin Cancer Res 2010;16(18); 4527–31

Increasing Cytotoxicity of TMZ and RT I i C t t i it f TMZ d RT • PARP Inhibitors – ABT 888 (ABTC; RTOG) ABT 888 (ABTC; RTOG) • Wee1 Inhibitor – MK1775

W Wee1 1 MK1775 G2 Arrest G2 progression and mitotic and mitotic catastrophe

Glioma Initiating Cells Wen PY, Kesari S. N Engl J Med 2008;359:492-507

Glioma Initiating Cells Wen PY, Kesari S. N Engl J Med 2008;359:492-507

BKM120+LDE225 In vivo data: orthotopic xenograft of PTEN ‐ deficient tumor f PTEN d fi i Mariella Gruber-Olipitz et al. Nature Med. In Press

Combo LDE225+BKM120 MA man NUM Hum

limited resources Many choices; h i M