Should novel molecular therapies replace old knowledge of clinical tumor biology?

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1 Should novel molecular therapies replace old knowledge of clinical tumor biology? Danai Daliani, M.D. Director, 1 st Oncology Clinic Euroclinic of Athens

2 Cancer Treatments Localized disease Surgery XRT Systemic disease Chemotherapy Pathology Clinical phenotype Variants not well defined Targeted therapy unique? driver? gene alteration Immunotherapy Host response

3 Precision Medicine Molecularly Targeted Agents Use Information about a person s genes, proteins, and environment to prevent, diagnose and treat disease. MTAs modulate the function of specific molecular targets in cell signaling Proliferation Apoptosis Angiogenesis Metabolism Migration Invasion

4 PROMISE of Personalized Cancer Medicine Non-toxic treatments Minimal long-term side effects Significant clinical benefit Cure without exposing many patients to unnecessary treatments Cost-effective

5 Successful Targeted Therapy Imatinib in BCR-ABL + CML (driver gene in most pts) Trastuzumab in Her-2-neu+ breast cancer Vemurafenib in BRAF V600E-mutated melanoma AR targeting in CRPCa ER targeting in BrCa VEGF (and mtor?) inhibition in RCC

6 But. ~ 50% of Her2-neu + pts do not respond / resistance develops in most in 2 yrs Definition of Her-2+ disease? Definition of ER+ BrCa (1% biologic significance of 99% of ER - tumor cells?) ARvs (and their subcellular localization response to Rx) BRAF-V600E mutant CRC? (activation of EGFR feedback loop) different functional significance across tumor types? (passenger mutations?) 40% of mrcc pts respond to VEGF inh but only a minority to mtor inh (who? ) Systems Biology take into account multiple molecular alterations to predict treatment efficacy (complex)

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10 Tumor samples from 4 RCC pts multiple sites - before and after Rx 2/3 mutations in single biopsies not detectable across all sampled regions of the tumor Different mutations in the same gene in different regions of the same tumor Tumors would do anything to activate / inactivate certain genes to increase fitness Kwiarkowski DJ, et al. (2016) Mutations in TCS1, TSC2 and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin Cancer Res 22(10): Divergent / Branched evolution in many tumors

11 Tumor Heterogeneity Every unhappy family is unhappy in its own way - Tolstoy in Anna Karenina Macroscopic: race, gender, age, tissue / organ Microscopic: histology, tumor microenvironment Molecular: genetic, epigenetic factors Intra-tumoral heterogeneity Inter-metastases heterogeneity

12 Somatic cell with heritable fitness-promoting mutation Proliferation Selection pressure from TME survival promoting mutations genetic divergence genomic instability

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14 Success of Personalized Medicine Less expensive Genome sequencing Hundreds (?) of biomarkers clinical significance? Smaller groups of patients Market? Research? Cost?

15 Questions?

16 Time and Space-ITH can lead to underestimation of the tumor genomics landscape portrayed from a single tumor-biopsy samples and may represent major challenge to personalized-medicine and biomarker development Possible Solutions: Target trunk lesions Stay ahead of epigenetic changes -> repeat biopsies sequential MTAs ( clinical significance?) Combination of MTAs (toxicity?) Met to Met Colonization / Spread

17 Potential Trial Designs 1. Select pts per tumor type Retrospective molecular analysis High No. pts exposed to drug 2. pre-inclusion tumor assessment central - sponsor Amount tumor tissue needed Uniplex sequencing time large No. Pts screened - cost 3. Local screen for target they fit High-throughput techniques Cost?

18 Challenges to Molecular Screening Programs Choice of Assay : # genes to sequence, time, ease of scalability, analytical validity, potential for research discoveries, cost - # genes / depth of sequencing Bioinformatics analysis Sample selection: tissue age, fixation time, size, mixture of cells / tumor cellularity Cost of genome sequencing: process analysis-interpretation loss of resources from other trials Ethical issues: medical, psychological, financial, social implications Distinguish: relevant findings to pt and relatives from incidental - Consent?

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20 Thoughts. Various tumor types Multiple lines of prior therapies Limited access to MTAs Most MTAs partial inhibition of signaling pathways Plasticity of signaling pathways adaptation / many molecular alterations technical issues ITH ctdna?- representative? Single agent Rx, but combinations too toxic Cost diverts resources from development of more effective therapies

21 Tannock and Hickman, NEJM 375:13; Need Well-designed collaborative programs to recognize and combat the limitations Clear message to patients that PM has not led to gains in survival or its quality Appropriate only within clinical trials

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25 Thank you