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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Symposium New Drugs on the Horizon Part 1 4:50- 6:00 pm

Reporter: Stephen J. Williams, PhD.

SESSION VSY.DDT01 – New Drugs on the Horizon: Part 1

April 27, 2020, 4:50 PM – 6:05 PM
Virtual Meeting: All Session Times Are U.S. EDT

Session Type
Virtual Symposium
Track(s)
Experimental and Molecular Therapeutics,Drug Development
10 Presentations
4:50 PM – 6:00 PM
– CochairAndrew J. Phillips. C4 Therapeutics, Watertown, MA

4:50 PM – 6:00 PM
– CochairMichael Brands. Bayer Pharma AG, Berlin, Germany

4:50 PM – 4:54 PM
– IntroductionAndrew J. Phillips. C4 Therapeutics, Watertown, MA

4:54 PM – 5:14 PM
DDT01-01 – A first-in-class Menin-MLL1 antagonist for the treatment of MLL-r and NPM1 mutant leukemias Jerry McGeehan. Syndax Pharmaceuticals, Inc., Waltham, MA

• Their inhibitor binds to C terminus of Menin MLL1 which is required for AML progression
• MLL-4 is from a translocation causing a fusion protein; the inhibitor block leukemic transcription program
• anti transcription program when Menin inhibitor is used; displaces Menin from chromatin

• worked in tumor models
• their inhibitors have good antiproliferative activity seems has good bio-availability in rat and dog
• they have active QT signal (cardiac tox) screen program in their clinical studies
• initial pre phase1 have not found the max effective dose
• not a complete response so may have to look at combination

5:14 PM – 5:17 PM
– Discussion

5:17 PM – 5:37 PM
DDT01-02 – BAY 2416964: The first Aryl Hydrocarbon Receptor (AhR) inhibitor to enter phase I clinical development as a novel cancer immunotherapy. Ilona Gutcher, Christina Kober, Julian Röwe, Ulrike Roehn, Lars Roese, Florian Prinz, Detlef Stoeckigt, Benjamin Bader, Matyas Gorjanacz, Rafael Carretero, Norbert Schmees, Horst Irlbacher, Helge Roider, Katharina Sahm, Hilmar Weinmann, Ingo V. Hartung, Bertolt Kreft, Rienk Offringa, Michael Platten. Bayer AG, Berlin, Germany, Bayer AG, Germany, DKFZ, Heidelberg, Germany

• has a more proinflammatory effect in vivo than other I/O inhibitors
• rescues TNF alpha immunomodulation
• further increases IL2 and IFN gamma when combined with I/O inhibitor so by a different mechanism
• looking to use in NSCLC
• prelim tox looks fine

5:37 PM – 5:40 PM
– Discussion

5:40 PM – 6:00 PM
DDT01-03 – IPN60090: A potent and selective inhibitor of glutaminase being developed for KEAP1/NFE2L2 mutant NSCLC and ASNS-low HGSOC patients. Jeffrey J. Kovacs. UT MD Anderson Cancer Center, Houston, TX

• Being developed for NSCLC and high grade serous ovarian cancer
• glutaminolysis repsonsible for many of the building blocks of cell function
• these compounds had selective antiproliferative but was focus on GLS1
• good PK and bioavailability; mouse half life is short but dog is longer so estimated human is 8 hours
• increased pentose phosphate pathway; reliance on GLS1 activity promotes metabolic reprogramming
• the inhibitor significantly reduced glutathione in responder cell lines; responders had higher level of ROS
• use ribose pathway and pentose shunt to help deal with REDOX
• get a antitumor response in KEAP mut PDX models and these PDX respond poorly to I/O checkpoint inhibitors
•  ASN2 was higher in nonresponders (alt. formation of Gln) as well as GPT2
• ASN2 high expressing nonresponding OVCA lines; need low ASN2 in OVCA for response
• so given metabolic plasticity used shRNA screens after inhibitor
• PI3K turned up so can use mTORC inhibitor in combo; works well with GLS1 inhibitor to inhibit tumorigenesis
• they are looking at other combos including std. chemo and I/O checkpoints
• currently doing dose escalation clinical study

6:00 PM – 6:04 PM
– Discussion

6:04 PM – 6:05 PM
– Closing Remarks Michael Brands. Bayer Pharma AG, Berlin, Germany

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