Anjani Shah, Ph.D., Conference Director, interviewed Dr. Lenny Dang from Agios and Dr. Raju Pasupati from Genentech, two speakers from our upcoming meeting, ‘Cancer Metabolism’ taking place in Boston, MA Oct. 9-10, 2014. The interviews took place over email in July of 2014.
Topics include the promise of new cancer targets such as IDH,metabolic transporters, Lactate Dehydrogenase (LDH), Glutaminase, Pyruvate Kinase M2 isoform (PKM2) mitochondrial enzymes and enzymes involved in one-carbon metabolism, over-coming cancer drug resistance and the possibility of combination therapies.
What do you think are the most promising targets/molecules/cellular pathways that are involved in the altered metabolism of tumor cells and can be used for screening anti-cancer agents?
Within the hub of central metabolism, I see two exciting areas for potential novel therapeutic discovery: metabolite transporters and the regulation of mitochondrial ROS (reactive oxygen species).
Targets that have promise: Mutant Isocitrate Dehydrogenase (IDH), Lactate Dehydrogenase (LDH), Glutaminase, Pyruvate Kinase M2 isoform (PKM2) Metabolic pathways of interest: mitochondrial metabolism, serine metabolism, glycine metabolism, one-carbon metabolism.
Do you feel there are more "undiscovered" druggable metabolic targets for compounds to address?
The most exciting emerging aspect of cancer metabolism is the gain in knowledge of the intricate interplay between metabolism, epigenetic regulators, oncogenic signaling network and to an extent cancer immunity. Inhibiting one of these processes in a specific context could uncover survival susceptibility of the others. As such, the future of cancer metabolism drug development will likely be done in combination with other modalities to achieve maximal and durable responses.
Yes, there remain targets to be discovered because only recently have we begun to unravel the role of common metabolic enzymes in cancer. Novel oncogenic mutations and cancer- specific isoforms of metabolic enzymes which are potential drug targets were discovered recently and more are likely to be discovered in the near future. The one-carbon metabolism pathway has druggable metabolic targets that I expect to be hearing more about in the near future.
What are the biggest hurdles/challenges in developing 'metabolic-targeted' compounds into anti-cancer therapeutics?
The biggest challenge in cancer metabolism at this stage is the nature of metabolic plasticity, redundancy and adaptation. This can be partly addressed by identifying cancer subtypes that are dependent on non-redundant metabolic nodes, such as chromosomal co-deletion of metabolic isozymes for example. Another practical challenge in discovery is the frequent disconnect between in vitro and in vivo metabolism. Extracellular nutrient conditions affect the response of most metabolic enzymes. Making sure the extracellular nutrient conditions are mimicked accurately in-vitro is a challenge.
Drug resistance is likely to be a challenge because metabolic pathways are highly interconnected and exhibit extensive cross talking. This gives an ability to cancer cells to quickly adapt to the inhibition of any one node in their metabolic pathways. Therefore I strongly feel that novel metabolism targeting anti-cancer agents will be more successful in combination rather than as single agents.
Which talks/issues at the meeting are you looking forward to learning more about?
Talks that I would be interested in are those related to mitochondria and include: Marcia Hagis's talk on mitochondrial acetylation, Ivana Kurelac's mitochondrial complex 1 presentation, as well as Marie Evangenlista's talk on LDHA inhibitors. These talks should well exemplify the therapeutic challenges as well as therapeutic opportunities in cancer metabolism.
I am particularly interested in the Session "Onco-Metabolic Candidates in Development". I am curious as to how glucose metabolism is targeted in cancer cells as it has been a very vexing problem for the past 50 years. From that perspective I am looking forward to Gilles Tapolsky's and Paul Bingham's talks.
Drugging Mutant IDH at the Crossroads of Cancer and 2HG Aciduria
Lenny Dang, Ph.D., Senior Director, Biochemistry, Agios Pharmaceuticals, Inc.
mTOR/S6K Pathway-Dependent Metabolic Reprogramming in Cancer Cells Mediates Resistance to Glycolytic Inhibitors
Raju Pusapati, Ph.D., Postdoctoral Research Fellow, Discovery Oncology (Jeff Settleman Lab), Genentech, Inc.