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Targeting Mitochondrial Dysfunction & Toxicity Conference - Day 2


2014 Archived Content

THURSDAY, MARCH 20 


Day 1 | Day 2 | Brochure 

7:45-8:20 am Morning Coffee

8:25 Chairperson’s Comments

Mark Bamberger, Ph.D., CSO, Stealth Peptides, Inc.

CANCER 

8:30 Isolated Normal Mitochondrial Organelle Transplantation to Cancer Cells

Robert L. Elliott, M.D., Elliott-Barnett-Head Breast Cancer Research and Treatment

In the 1930s, Otto Warburg demonstrated mitochondrial dysfunction and defective respiration in cancer cells. Cancer cells have a glycolytic phenotype with increased glucose uptake. Isolated normal mitochondria rapidly enter cancer cells. This uptake inhibits proliferation, glycolysis, and increases drug sensitivity. We believe that isolated normal mitochondria could be utilized as a biological nanoparticle for cancer therapy. Our mitochondrial organelle transplantation of normal isolated mitochondria to cancer cells supports Warburg’s theory that cancer is a metabolic disease caused by defective mitochondria.

9:00 Targeting Mitochondrial Function for the Treatment of Breast Cancer

Paola Marignani, Ph.D., Associate Professor, Biochemistry and Molecular Biology, Dalhousie University

Numerous studies have shown a correlation between mitochondria dysfunction and aberrant signaling pathways that give rise to disease. As such, we have re-engineered a mouse to develop breast cancer that is hyperactive for mTOR and metabolically active. With this new tool, we are conducting preclinical trials to test combinations of drugs that target hyperactive mTOR and cancer cell metabolism in our model of breast cancer.

9:30 The Role of mtDNA Mutations in Keratinocyte Neoplasia

Jana Jandova, Ph.D., Research Instructor, University of Arizona

This presentation will show the importance of mtDNA alterations in finding of novel, more effective agents for skin photo protection and identifying new potential targets for skin cancer chemoprevention since there is an increasing evidence of skin cancers in the U.S and solar UV-radiation is a major environmental carcinogen.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing


DIABETES AND METABOLIC DISORDERS 

10:30 Mechanisms of Biguanides as Anti-Diabetic and Candidate Anti-Neoplastic Drugs

Michael Pollak, M.D., McGill University-Montreal

Metformin is a widely used drug in treatment of type II diabetes, and also the most widely used drug with a mitochondrial target. Recent work clarifies how biguanides such as metformin, phenformin and others accumulate in mitochondria, where they partially inhibit function of complex I , resulting in a wide range of cell-lineage-specific consequences. For type II diabetes treatment, the reduction in hepatic gluconeogenesis is of key importance. Pharmacoepidemiologic data has raised the hypothesis that biguanides have antineoplastic activity, and this has been demonstrated in several laboratory models. Consequences of exposing cancer cells to biguanides can include an energetic crisis and necrotic cell death in cells poorly tolerant of energetic stress, or a cytotostatic effect in cells that compensate by activating AMPK and inhibiting mTOR. While many clinical trials of metformin for cancer treatment have been initiated, pharmacokinetic properties of this biguanide may not be optimum for this indication, and novel biguanides are being studied preclinically.

11:00 New Drug Discovery:  Induction of Protective Genes Against Unwanted Toxicity to the Mithochondria

Grace Wong, Ph.D., CEO ActoKine Therapeutics

ActoKine Therapeutics has discovered that ActoKine 1 (AK-1) can induce the expression of manganous superoxide dismutase (MnSOD). MnSOD, identified as one of the protective proteins, is a mitochondrial enzyme that scavenges superoxide radicals (O2−). Overexpression of MnSOD but not CuZn-SOD or EC-SOD enhances cellular resistance to radiation & chemotherapeutic drugs. Conversely, silencing MnSOD RNA diminishes cellular protection. Transfection of cells with MnSOD lacking the mitochondrial matrix signal does not provide protection against radiation or cancer drugs. However, insertion of the mitochondrial signal sequence into CuZn-SOD or EC-SOD results in significant protection. AK-1 does not induce MnSOD in tumor cells; nor does AK-1 protect the tumor cells against radiation or cancer drugs. Actually, AK-1 pretreatment can sensitize tumor cells to killing by radiation or chemotherapeutic drugs.

11:30 Targeting Mitochondrial Dysfunction with Bendavia: A Novel First-in-Class Therapeutic

Mark Bamberger, Ph.D., CSO, Stealth Peptides, Inc.

Bendavia is a first-in-class mitochondrial therapeutic that has demonstrated efficacy in a number of disease models, including acute coronary syndrome, acute and chronic kidney disease, heart failure and neurodegeneration. By selectively interacting with the inner mitochondrial membrane, Bendavia normalizes electron flux and ATP levels, while reducing the production of reactive oxygen species in dysfunctional mitochondria, without affecting healthy mitochondria. The clinical potential of Bendavia is currently being assessed in several Phase 2 trials in the U.S. and Europe.

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own


AVOIDING MITOCHONDRIAL TOXICITY 

1:55 Chairperson’s Comments

Yvonne Will, Ph.D., Compound Safety Prediction- WWMC, Cell Based Assays and Mitochondrial Biology, Pfizer R&D

2:00 In vitro Approaches to Assess Mitochondrial Toxicity and Mitochondria-Mediated Drug Toxicity: A Decade of Learning

Yvonne Will, Ph.D., Compound Safety Prediction- WWMC, Cell Based Assays and Mitochondrial Biology, Pfizer R&D

2:30 Novel Tools to Assess Mitochondrial Toxicity Under Physiological Conditions

Nagendra Yadava, Ph.D., Principal Investigator, Pioneer Valley Life Sciences Institute

Mitochondrial toxicity is the major cause for the failure of drugs. Therefore, early screening of drugs for mitochondrial safety under physiological conditions is essential. In this talk, I plan to discuss; 1) a novel technology to assess mitochondrial function in cell cultures that eliminates the need for isolated mitochondria following permeabilization with perfringolysin-O (a pore forming cytolysin); and 2) a novel Ndufa1S55A allele knock- in mouse model with systemic respiratory chain Complex I insufficiency to assess drugs sensitivity in vivo.

3:00 Metabolically-Modified Liver Models to Examine the Role of Mitochondrial Dysfunction in Drug-Induced Liver Injury

Amy Chadwick, MChem, Ph.D., Tenure Track Fellow, Institute of Translational Medicine, The University of Liverpool

This presentation will showcase data from the MIP-DILI consortium of 26 participants from the pharmaceutical industry, SMEs and academic institutions. This objective of this unique consortium is to develop and evaluate innovative preclinical test systems to improve the current test-systems which are poorly predictive of DILI, which is a major health problem (global incidence of 13.9 per 100 000 inhabitants/year). Drug-induced mitochondrial dysfunction has been hypothesized to be a determining link in the onset of such idiosyncratic DILI and 50% of drugs with Black Box Warnings for DILI contain mitochondrial liabilities. We will provide an overview of the MIP-DILI project goals and objectives and will show how our mechanistic mitochondrial toxicity data form part of a larger effort to better predict DILI.

3:30 Assessment of Drug-Induced Mitochondrial Dysfunction via Altered Cellular Respiration and Acidification Measured in a 96-Well Platform.

Sashi Nadanaciva, Ph.D., Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer, Inc.

High-throughput applicable screens for identifying drug-induced mitochondrial impairment are necessary in the pharmaceutical industry. Hence, we evaluated the XF96 Extracellular Flux Analyzer, a 96-well platform that measures changes in the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of cells. The sensitivity of the platform was bench-marked with known modulators of oxidative phosphorylation and glycolysis. We show that the XF96 platform is a robust, sensitive system for analyzing drug-induced mitochondrial impairment in whole cells. We identified changes in cellular respiration and acidification upon addition of therapeutic agents reported to have a mitochondrial effect.

4:00 Closing Comments

4:15 End of Conference

 

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