Chad Pecot, MD
@ChadPecot
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Cancer Killer | Engineering RNA medicines to End Cancer | Potentially sarcastic | Honey-badger
Outside the box
Joined June 2020
Now in @Cancer_Cell our group reports the development of a first-in-class EGFR-directed KRAS G12V selective inhibitor. KRAS G12V mutations are the 2nd most common KRAS mutation in cancer, and there are still no approved inhibitors in the clinic. We address two major challenges
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RT @oncodaily: Development of the First Dual KRAS+MYC Inhibitor - Chad Pecot (@ChadPecot). #Cancer #Oncology #Onco….
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I’m very proud of newly minted Dr. Yogitha Chareddy, who led this effort, along with much of my team. Grateful for collaborations with Albert Bowers and Martin Egli (Vandy). I’m very appreciative of the reviewers and editors at @jclinicalinvest for helping shape this paper. And.
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Finally, recent work by @KenOliveLab et al demonstrated MYC copy number gains are a mechanism of resistance to pan-KRASi (RMC-7977): Consistent with this, we observed KRAS RNAi did not affect several RMC-7977 resistant lines, however, MYC RNAi and
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Evaluating for potential mechanisms of resistance to single KRAS, MYC or dual KRAS/MYC inhibition, we observed:. - KRASi: Over-expression of KRAS.- MYCi: Decreased pYAP1 S127; increased total YAP.- KRAS/MYCi: Decreased pYAP1 S127; increased total YAP.- Note: Dual KRAS/MYCi
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Using a KRAS G12C mutant lung model, we found the inverted KRAS/MYC chimera performed on a comparable level as sotorasib, the first FDA-approved KRAS G12C inhibitor. Due to the distinct modalities (RNAi to silence KRAS mRNA v. small molecule to block KRAS protein signaling), we
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Another interesting observation came when we measured anti-sense strands for KRAS and MYC in tumors. The chimeras resulted in markedly increased accumulation in tumors (~30-fold increase) compared with single siRNA targeting, resulting in ~70-80% mRNA silencing of both targets.
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This paper has a lot of in vivo characterization too! Although dual KRAS+MYC targeting was synergistic in vitro, it had more of an additive effect in vivo. Using a non-targeting control peptide, we confirmed our EGFR-directed delivery platform is necessary for effective chimera
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Using structural modeling, we determined it’d likely be a requirement for the thymidine bridge to be cleaved in order to load into Ago2. We experimentally validated this using a non-cleavable phosphorothioate bridge. Interestingly, we found that 5’-antisense dT overhangs
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Using a luciferase reporter, compared with single KRAS siRNAs, the inverted chimeras demonstrated marked improvement in potency. Also, for several KRAS mutant cell lines, although individual KRAS and MYC siRNAs showed potent inhibition of cell viability, the inverted chimeras
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Stability assays demonstrated the chimeras are cleaved in the endosomes and are quite stable in plasma and the cytosol, and cleavage is pH independent. Using an EGFR-directed ligand conjugate design, the inverted chimeras essentially function like a targeted, 2-in-1 “pro-drug”,
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Next, to realize a dual KRAS/MYC RNAi strategy, we considered 2 orientations of siRNAs:.· Inverted design: 2 siRNAs in a “mirror image”, separated by a 4-thymidine bridge.· Serial design: 2 siRNAs in tandem separated by a 4-thymidine bridge. Unexpectedly, the inverted design was
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First, we did lots of work to develop potent MYC RNAi molecules with “drug-like” properties. We arrived at two highly potent drug candidates (Mseq2 and Mseq3). (3/13)
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This work builds upon our recent study characterizing development of an EGFR-directed KRAS G12V mutant selective RNAi molecule (EFTX-G12V). Because mutant KRAS signaling activates MYC through several mechanisms, we evaluated whether co-targeting of KRAS.
Now in @Cancer_Cell our group reports the development of a first-in-class EGFR-directed KRAS G12V selective inhibitor. KRAS G12V mutations are the 2nd most common KRAS mutation in cancer, and there are still no approved inhibitors in the clinic. We address two major challenges
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What’s better than drugging one “undruggable” target? How about drugging 2 at the same time!. Now out in JCI our group reports the development of the first dual KRAS+MYC inhibitor. Here are some key highlights 👇
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Due to a high volume of emails, I am no longer responding. 🫶.
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RT @lpachter: This week in academia, a not so short🧵. 1. Staff reductions and other cost cutting measures coming to Brown University ht….
highereddive.com
The Ivy League institution's top officials signaled possible staff reductions along with scaled back capital spending and other measures.
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RT @UNC_Lineberger: .@ChadPecot, MD, and colleagues have demonstrated that a uniquely engineered drug that zeroes in on a mutated gene call….
unclineberger.org
Chad Pecot, MD, and colleagues have demonstrated that a uniquely engineered drug that zeroes in on a mutated gene called KRAS G12V could potentially stop KRAS-dependent cancers in their tracks.
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This was a massive effort over many years led by Lyla Stanland and Hayden Huggins. Grateful to the hard work of my lab and excellent collaborators, Justin Milner, Martin Egli and Albert Bowers. Thanks so much to the reviewers who truly made the paper more robust and challenged us.
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Because complete inhibition of mutant KRAS is challenging with any modality, we evaluated whether dual KRAS blockade with EFTX-G12V (RNAi-mediated silencing) and RMC-7977 (allosteric inhibition) could improve MAPK inhibition. We observed an additive or synergistic effect in
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