Targeting Cancer Pathways: Tumor Resistance

Participating Experts: Michael Yaffe MD, PhD (MIT), Jeffrey Engleman MD, PhD (Harvard Medical School), and Michael Deininger MD, PhD (U. Utah) ⬇️ Expand “Show More” to view abstract and table of contents:
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Recent advances in our understanding of cancer have revealed that the disease cannot be understood through simple analysis of genetic mutations within cancerous cells. Instead, tumors should be considered complex tissues in which the cancer cells evolve and communicate with the surrounding cellular microenvironment to promote their own survival and dissemination. Although therapies against specific signaling proteins or pathways have been remarkably successful at treating certain cancers, the tumors frequently develop resistance, leading to even more aggressive forms of the disease. This webinar focuses on how rewiring of signaling pathways in response to drug treatment contributes to resistance and how this knowledge can be leveraged to develop more effective treatment strategies. Topics covered include:
• the specific molecules and pathways that are the targets for rationally designed therapies;
• efforts to overcome resistance to the first FDA-approved therapy targeting a hyperactive kinase;
• mechanisms by which tumor cells resist inhibitors that target cell survival and growth pathways;
• how the rewiring of cell death pathways can sensitize cells to traditional chemotherapy agents.

Table of Contents
0:00 Welcome and Introduction
2:44 Michael Yaffe speaker profile
3:39 Dynamic re-wiring of signaling networks as mechanisms for improving combination therapy for cancer
4:28 Signaling and systems biology - missing data that links genotype to phenotype
6:14 Static vs dynamic network rewiring
7:35 Combination drug screen for triple negative breast cancer
8:44 Efficacy of EGFR inhibition in BT-20 cells depends on timing of drug delivery
9:34 Subtype dependent responses to treatment
10:35 Understanding dynamic re-wiring – role of apoptosis
11:58 Working model
13:12 Nanoparticle development for time-staggered drug delivery in vivo
14:32 Combination erlotinib-doxorubicin nanoparticles in vivo
16:24 Generalizing time-staggered inhibition of RTK signaling for tumor sensitization
18:20 Conclusions
20:04 Jeffrey Engleman speaker profile
21:03 Resistance to tyrosine kinase inhibitors in lung cancer
21:41 Cancers with EGFR mutations are highly sensitive to EGFR kinase inhibitors
22:27 Cancers with ALK translocations are highly sensitive to ALK kinase inhibitors
26:03 Acquired resistance to targeted therapies
23:47 Sensitivity to tyrosine kinase inhibitors
28:48 One-third of crizotinib-resistant tumors harbor ALK resistance mutations
29:26 Spectrum of resistance mechanisms – results from repeat biopsy program
31:29 Serial biopsies reveal dynamic populations of different clones
33:15 Multiple populations in a single tumor nodule
36:07 Antitumor efficacy of ceritinib
36:51 Selection of new resistant clones on LDK378 (certinib)
37:57 Develop regimens: alternating and intermittent therapeutic combinations
39:44 Michael Deininger speaker profile
40:34 Protein kinases regulate key cell functions
41:22 Chronic myeloid leukemia (CML)
42:56 BCR-ABL kinase activity is central to CML pathogenesis
43:56 Imatinib improves survival in CML
44:40 BCR-ABL1 tyrosine kinase inhibitors (TKI)
47:03 Mechanisms of TKI resistance
48:20 Resistance mutations in BCR-ABL1
49:56 Preclinical characterization of Ponatinib
51:20 Accelerated mutagenesis screen: predicting mutation resistance to TKIs
53:49 Ponatinib Phase 2 study
55:47 T3151-inclusive compound mutations confer universal TKI resistance
58:48 Forcing BCR-ABL to commit mutational suicide
1:00:53 Auto-inhibition of ABL kinase activity
1:02:37 Inhibition of T315I in vitro with GNF-5 plus nilotinib
1:04:19 Questions and answers

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