Malignant cells are under increased mitochondrial stress through mechanisms such as hypoxia, oxidative damage, altered metabolism, and mitochondrial protein damage and misfolding. Using evolutionary conserved pathways including anti-oxidants, anti-apoptotic pathways, proteases, and protein chaperones, mitochondria have developed mechanisms to survive and proliferate amidst these stressors.  Studies in model organisms such as worms have provided important biologic insights into these mitochondrial stress pathways, including how they regulate longevity.  Fundamental and preclinical studies in malignancy have shown that disrupting mitochondrial stress pathways selectively kill subsets of malignant cells over normal cells. Finally, strategies that target mitochondrial stress have advanced to clinical trials for patients with cancer and show promising clinical efficacy.

Yet, important questions remain unanswered. For example:

• How do mitochondrial stress pathways influence longevity in model organisms?
• What are the functions of components of mitochondrial stress pathways in cancer cells?
• Why and how does targeting mitochondrial stress pathways selectively eradicate malignant cells over normal cells?
• Which cancer patients are most and least dependent on which mitochondrial stress pathways?

This meeting will bring together a multidisciplinary group of researchers to discuss mitochondrial stress in cancer and spark collaborations from investigators in diverse fields who would likely not otherwise interact.

Session 1:
“Mitochondrial stress pathways in model organisms - insights into pathways and targets” will discuss mitochondrial stress in model organisms. It will highlight new pathways by which worms and yeast cope with mitochondrial stress and how these pathways impact longevity.

Session 2:
“Novel pathways and cancer targets in mitochonrial stress” will discuss the biology of the mitochondrial stress pathways in malignancy. We will highlight new regulator of mitochondrial stress such as mitochondrial proteases and mitophagy and the biological rationale for a therapeutic window in targeting these pathways

Session 3:
“Preclinical studies and translational opportunities targeting mitochondrial stress in cancer” will highlight the translational opportunities to target mitochondrial stress pathways in malignancy. This session will include discussion on novel drug combinations that target mitochondrial stress pathway

Session 4:
“Mitochondrial Stress in Cancer Clinical trials” will highlight clinical trials with mitochondrial stress inducing drugs. This session will include clinical studies with Venetoclax that is now approved for the treatment of malignancy. In addition, it will explore novel agents such as the mitochondrial heat shock inhibitor, gamitrinib and the ClpP inhibitor ONC201 that have advanced into clinical trial with promising results. This session will discuss which patients are most and least likely to respond and markers that can predict response to these drugs.

RELEVANCY

Targeting mitochondrial stress pathways is an emerging therapeutic strategy that has advance to clinical trial. Some of these drugs have shown promising efficacy while others have failed to produce clinical benefit due to increased toxicity. The successful development of drugs targeting mitochondrial stress pathways will require a greater understanding of the biology of these pathways, including insights from model organisms. This meeting will bring together a diverse and multidisciplinary group to discuss mitochondrial stress in cancer. This will be a unique opportunity to bring together investigators studying model organisms with cancer biologists and clinical trialists. It will spark collaborations and the sharing of information between scientists who would not otherwise interact. This meeting is particularly timely given the clinical approvals of Venetoclax in AML and the early clinical trials of gamitrinib and Onc201 in patients with advanced solid tumors. These agents already demonstrate the importance and clinical benefit of targeting mitochondrial stress in cancer.  To date, there has not been a similar Forbeck conference.

GOALS

The meeting will have the following objectives;

1. To bring together a diverse group of scientists and clinicians who are engaged in studies of mitochondrial stress at the level of model organisms, cells and patients
2. To spark collaborations among investigators who might not otherwise interact
3. To gain insights into pathways that defend against mitochondrial stress in model organisms and how these pathways might impact cancer cells
4. To identify targets in mitochondrial stress pathways whose inhibition would preferentially eradicate malignant cells
5. To identify the subset of malignancies and patients that would be most and least likely to respond to induction of mitochondrial stress