5/8/2015. Disclosures. Personalized Medicine & Pediatric Oncology: Is the Future Here Yet? Objectives

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1 Disclosures Personalized Medicine & Pediatric Oncology: Is the Future Here Yet? Richard Drachtman, MD NJAAP Annual Conference May 13, 2015 Research Support: Mast, Astra Zeneca, Jazz, Novartis, Pfizer Objectives Review the status of precision medicine in pediatric oncology Review the history of targeted therapy in oncology Potential application of targeted therapies to the pediatric population Pros/Cons of targeted therapy What I won t do: Give an exhaustive review of precision medicine in lung/breast/colon cancer 1

2 Is the future here already, and how long have we been there? What is Precision Medicine? Cellular and molecular analyses immunophenotype, immunohistochemistry cytogenetics, molecular analyses are used to classify cancer Refinements in the classification and understanding of the pathogenesis/pathophysiology are resulting in the development of new targeted therapies Tailoring therapeutics for an individual based on pharmacogenetics and pharmacogenomics Academic Perception of Personalized Therapeutics More accurate diagnosis and treatment of disease More precise risk stratification More effective and less toxic therapy Reduced Toxicity to normal tissues Potential for superior outcomes Possibility of decreased late effects Slide courtesy of Jocelyn Lewis, DO 2

3 Public Perception of Personalized Therapeutics Historical Advances in Cancer Chemotherapy Cancer Res November 1, ; 8643 Historical Advances in Cancer Chemotherapy Cancer Res November 1, ; 8643 NORMAL CHEMO THERAPY LEUKEMIA 1955 Chevrolet CELL DAMAGE CELL DAMAGE Key regulatory pathways that detect DNA, protein and membrane damage Cell cycle arrest REPAIR Some key regulatory pathways that detect DNA, protein and membrane damage are mutated during oncogenesis Less Cell Cycle Arrest Enhanced damage --- apoptosis, mitotic catastrophe, prolonged arrest Slide courtesy of Roger Strair, MD, PhD 3

4 1955 Chevrolet 1955 Chevrolet - Modified for Racing Ideal drive Environment good Turn ignition Release standard and emergency brakes Put car in drive Step on gas Standard brakes removed Emergency brake disabled Gas pedal floors easily Stalling mechanism inhibited Harder to pull the car over Go faster but harder to control Chemotherapy Damage to the car: steering wheel damaged/tire rim dented Normally the car pulled over if out of control Standard brakes broken Emergency brake broken Gas pedal stuck Much harder to pull the car over for repair - compounds damage Why Chemotherapy Doesn't Work Doesn't target problem OR The car doesn't respond to the damage (downstream problem) OR Too much damage to unmodified car Cytogenetics and prognosis in ALL Favorable Hyperdiploidy >50, t(12;21) Chemotherapy in general is targeted therapy Intermediate Hyperdiploidy 47-50, Normal, del(6q), rearrangements of 8q24 Poor Hypodyploidy/near haploidy; near tetraploidy, del(17p), t(9;22), t(11q23) 4

5 Estimated frequency of specific genotypes in childhood leukemias. Types of Cytogenetic Abnormalities Gain or Loss of Chromosomes Structural Mutation Translocations Deletions Insertions Inversions Pui C et al. JCO 2011;29: by American Society of Clinical Oncology Leukemogenic Pathways Proliferative Advantage Impair Differentiation Interfere with Cell Cycle Provide Self Renewal Capacity Point Mutations Tandem repeat in FLT-3 (fms like tyrosine kinase) - 24% AML Promote Proliferation CCAAT/enhancer binding protein-alpha (C/EBPalpha)- 8% AML Block Differentiation Cytogenetic Techniques 1970s- Chromosomal banding 1980s- Fluorescent in-situ Hybridization 1990s- Comparative Genomic Hybridization 2000s- High Resolution Assays Targeted therapy in Oncology is not a new concept Acute Promyelocytic Leukemia PML-RAR-a protein provides a target for All Trans Retinoic Acid (ATRA) Mid 1990s ATO identified as additional therapy aimed at PML-RARa ATRA Leads to differentiation of PML cells to mature hematologic cells ATO degradation of APL cells 5

6 CML: a Disease Linked to a Single Molecular Abnormality CML Proliferative disorder of hematopoietic stem cells Well-characterized clinical course Philadelphia (Ph) chromosome Unique chromosomal abnormality Bcr-Abl tyrosine kinase A single molecular abnormality that causes transformation of a hematopoietic progenitor into a malignant clone The Ph Chromosome and the bcr-abl Gene History of TKIs abl 9 22 bcr 9 q+ t(9;22) translocation Ph (or 22q-) bcr-abl FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY Chromosome 22 c- bcr Exons Introns CML Breakpoints ALL Breakpoints Chromosome c-abl p210bcr-abl p185bcr-abl bcr-abl gene structure Nature Reviews Cancer 4, (May 2004) doi: /nrc s the first primary structure of a receptor tyrosine kinase, the epidermal growth factor receptor, was elucidated. 1990s Imatinib developed by Nicholas Lydon and Brian Druker 2001 Imatinib granted FDA approval for treatment of CML Tyrosine Kinase activation uic.edu 6

7 Imatinib For CML Tyrosine Kinase Inhibitor in Action Patient with GIST Transformation of Hematopoietic Cells in the Pathogenesis of ALL. Kinase Fusions Identified in Ph-like Acute Lymphoblastic Leukemia Pui C et al. N Engl J Med 2004;350: Roberts KG et al. N Engl J Med 2014;371: T-Cell Leukemia Overall survival probability by treatment era for patients enrolled onto Children's Oncology Group trials in , , and % patients have identifiable abnormalities T-cell receptor loci (14q11 and 7q34 or 7p14 Oncogenes juxtaposed to promoters Loss of upstream transcription regulators Other abnormalities: Episomal amplification of ABL1 Upregulation of MYB gene (chromosome 6) Hunger S P et al. JCO 2012;30: by American Society of Clinical Oncology 7

8 Kaplan Meier Analysis of Event-free Survival According to the Subtype of Leukemia in 467 Children with ALL Who Were Enrolled in Three Consecutive Treatment Protocols at St. Jude Children's Research Hospital from 1991 to Minimal Residual Disease Classic assessment of response to therapy is based on the percentage of blasts observed in the bone marrow at end induction >5% blasts considered incomplete response (M2) >25% blasts considered induction failure (M3) Very poor sensitivity- only 1-2% of patients are induction failures Pui C et al. N Engl J Med 2004;350: The Challenge of MRD MRD is the single most important prognostic factor in childhood ALL However, there is no evidence to date that using MRD to stratify therapy will either improve outcome or reduce toxicity How can we best utilize MRD determination in designing treatment for ALL? MRD Stratification Is there a group of patients for whom negative MRD at 1 or 2 time points warrants therapy reduction? Is there a clinical imperative for therapy reduction? Can patients with persistently positive MRD be salvaged with more aggressive therapy and/or bone marrow transplant? What is the best therapy for the largest subgroup of patients who are initially MRD positive but become MRD negative within 3 months? Advantages of Non Morphologic Blasts Identification Objective Increased Sensitivity Morphology - 1 in 20 cells Flow - 1 in 10,000 cells PCR - 1 in 100,000 cells Morphologic Assessment of Response Is Subjective Are the blasts really leukemia cells What constitutes a blast Not all hematopathologists are created equal Not all centers have luxury of hematopathologists 8

9 What I looked like as fellow reading slides Non-Morphologic Identification of Blasts Each leukemia clone is characterized by a unique immunoglobulin receptor (B precursor) or T cell receptordetectable by PCR Technique Each leukemic clone characterized by an aberrant surface protein expression signature Detectable by flow cytometry A schematic of current approach to anti-cd19 CAR T cell therapy is shown Blinatumomab is a novel bispecific construct that reacts simultaneously to normal CD3+ T cells and CD19+ ALL cells, creating a tight intercellular connection followed by T cell mediated cytotoxicity exerted on CD19+ blast cells (BiTE mechanism).2 The drug i... Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-cd19 chimeric antigen receptors Nat. Rev. Clin. Oncol. doi: /nrclinonc Renato Bassan Blood 2012;120: by American Society of Hematology 9

10 Towards Directed Therapy Monoclonal antibodies Vaccines Small Molecule Drugs Cellular therapies Inhibitors of specific function Non-myeloablative allogeneic hematopoietic stem cell transplantation Gene Therapy Small Molecule Drugs Tyrosine Kinase Inhibitors mtor inhibitors Proteasome Inhibitors PARP inhibitors Mammalian Target of Rapamycin (mtor) Inhibition Commonly used mtor inhibitors Sirolimus Temsirolimus Everolimus Ridafirolimus Everolimus in Action Proteasome Inhibitors Orlowski R Z, and Kuhn D J Clin Cancer Res 2008;14: by American Association for Cancer Research 10

11 Current Proteasome Inhibitors in Pediatrics PARP Inhibitors Bortezomib T cell lymphoblastic leukemia and lymphoblastic lymphoma trials Acute Myeloid leukemia with high FLT3/ITD ratio PARP Inhibitor Use Currently under early phase trials for solid tumors Shows promise in Ewing Sarcoma and nonrhabdomyosarcoma sarcomas in pre-clinical trials Phase II trials in progress Antibody Therapy in Pediatrics Chimeric antibody CH (now approved as Unituxin) Rituximab Antibody-Drug Conjugate Brentuximab-vedotin Evidence for Antibody Therapy Potential therapeutic targets: Reed-Sternberg surface markers, intracellular signaling pathways, and the tumor microenvironment J Natl Compr Canc Netw (2013) 11:8;

12 Secondary end points of overall survival (A) and progression-free survival (B) Younes A et al. JCO 2012;30: Progression-free survival (PFS) achieved with brentuximab vedotin compared with PFS achieved with the last prior therapy Targeted Therapy for HD?? JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma Roosboreck et al Blood April 14, 2011 vol. 117 no Younes A et al. JCO 2012;30: by American Society of Clinical Oncology Current COG Trials That Include Targeted Therapy Current COG Trials That Include Targeted Therapy Study # Phase Disease Drug Mechanism AALL T-ALL Bortezomib Proteasome Inhibition ADVL Relapsed ALL + Temsirolimus MTOR inhibitor NHL ADVL Refractory recurrent malignancies BMN 673 PARP inhibitor AAML AML with High allelic ration FLT3/ITD ADVL Relapsed/refracto ry solid tumors and ALCL ADVL Recurrent/refracto ry solid tumors Bortezomib + Sorafenib PF Cabozatinib Proteasome inhibition MTOR inhibitor Inhibitor of ALK and C-MET Tyrosine kinase inhibition ADVL DIPG AZD1775 Wee 1 Kinase inhibitor Study # Phase Disease Drug Mechanism ADVL Relapsed/refractory solid tumors ADVL Recurrent/refractory solid tumors ADVL Relapsed/refractory solid tumors ADVL Relapsed/refractory solid tumors AOST Recurrent/refractory Osteosarcoma AZD1775 MORAb-004 Eribulin Axitinib Eribulin Wee 1 Kinase inhibitor Humanized IgG 1k antibody against endosialin/tumor endothelial marker 1 Microtubule targeting agent TKI targeting VEGF Microtubule targeting agent 12

13 Current COG Trials That Include Targeted Therapy Study # Phase Disease Drug Mechanism ARST Nonrhabdomyosarcoma soft tissue sarcoma Pazopanib Multi-targeting TKI AHEP Hepatoblastoma Temsirolimus MTOR inhibitor AHOD Hodgkin Lymphoma Brentuximab vedotin Anti CD 30 antibody-drug conjugate ANBL Neuroblastoma CH Anti-GD2 antibody ANHL 12P1 2 Anaplastic Large Cell Lymphoma Brentuximab vedotin Crizotinib Anti CD 30 antibody-drug conjugate ALK inhibitor AALL Pre B ALL Blinatumomab BiTE antibody targets CD19 AALL PH + ALL Dasatinib TKI Foundation Medicine Purpose of Sending Tumor tissue to Foundation medicine Provides a fully informative genomic profile that helps physicians make treatment decisions for patients with cancer by identifying the molecular growth drivers of their cancers and helping oncologists match them with relevant targeted therapeutic options. When is Tissue Sent? Rare tumors Disease relapse Treatment failure Time of surgery Current Targeted Therapies Under Investigation for use in Pediatric Patients Targets for Kinase Inhibition: KIT, BCR-ABL, PDGFR, VEGF, RET, CSF-1R, FLT-3, EGFR, ERBB2, JAK2V617F, BCR-ABL, SRC, Lyn, FAK, Raf, VEGFR, ALK, mtor, Sonic Hedgehog, Aurora Kinase A, Smoothened Drugs for Kinase Inhibition Imatinib, Sunitinib, Gefitinib, Erlotinib, Dasatinib, Lapatinib, Sorafenib, Crizotinib, Temsirolimus, Everolimus, Sirolimus, GDC-0449, MLN8237, LDE225, Pazopanib Current Targeted Therapies Under Investigation for use in Pediatric Patients Antibody CH14.18 Blinatumomab Herceptin Cetuximab IMC-A12 Bevacizumab Target GD2 CD19 HER2 EGFR IGF-1R VEGF Pros and Cons of Targeted Therapy Pros Druggable Targets Available drug to target particular receptor Less toxicity Hope for patients with refractory disease Cons Druggable Targets No drug available Drug does not have any effect on the intended target Drug does not actually work on the intended target Lack of Animal Models Unknown downstream effects Side/Late effects in Pediatric Patients Targets that exist but don t confer a benefit in Pediatric tumors Trastuzumab aka Herceptin Proven clinical benefit in Human Epidermal Growth factor receptor HER-2 positive breast cancers HER-2 shown to be present in some patients with Osteosarcoma and is associated with chemotherapy resistance and poor prognosis A phase II trial tested Trastuzumab in HER 2 positive and negative patients in combination with conventional chemotherapy and did not show any survival advantage 13

14 Mechanisms Other than Proposed Targets Sonic Hedgehog Pathway Sonic Hedgehog Pathway In the human brain, Hh leads to delayed neuronal differentiation and increased proliferation of cerebellar granular neuronal precursors most importantly in the development of the external germinal layer (EGL)of the cerebellum While this process is controlled by a series of inhibitory steps in normal human brain development, in medulloblastoma, this pathway undergoes aberrant activation and increased upregulation of the SHh pathway and growth of medulloblastoma scienceblogs.com/pharyngula/2008/08/basics_sonic_hedgehog.php 9 Sonic Hedgehog Inhibitors Cyclopamine Sonic Hedgehog Inhibitors While the SHh inhibitors should directly target SHh or smoothened, we showed in our lab that Cyclopamine did not actually target SHh via Smoothened Proved this by selective knock down of Smoothened Had the same results and similar cell death Proved that mechanism was via reactive nitrogen species and not through inhibition of smoothened It does appear, however that LDE225 and GDC0449 do function on the intended targets LDE225 (Sonidegib) GDC0449 (Vismodegib) Research in Process Pros and Limitations of RNA-Seq Project goal: Offer DNA and RNA sequencing of tumor genome and transcriptome to patients who: Fail treatment Have no salvage therapy expected to confer a 5-year event-free survival >20% Identify actionable molecular alterations for which existing therapeutic agents are available Offer a therapy which would not previously been considered in order to improve patient outcomes Clear up Indeterminate copy number alterations ( 8) results from Foundation Medicine Increased expression with copy number alterations of 4-6 could warrant treatment Check gene expression before and after treatment EGFR increased KRAS/BRAF expression? Unknown up-regulation of oncogenes with no mutations Need to use tissue with same histology as tumor type Signet ring cell adenocarcinoma sparse cells in normal ileum Could be a problem with metastatic disease to lymph nodes or other organs Need to confirm upregulated genes with no apparent mutations using either IHC (if available) or qpcr that s already clinically validated 14

15 Future Directions RNA sequencing Comparison of alterations in primary tumor vs. relapsed tumor Examination of epigenetic alterations Drug development Long term follow up Application to non-oncologic diseases Limitations to Personalized Medicine Cost Insurance Coverage Hugs for Brady at CINJ Lack of mutations/actionable targets Lack of Animal Models Unknown downstream effects Drug development / FDA approval 15