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This work was led by Kaitlin Long, a phenomenal undergrad/tech in my lab. Many of you reading these tweets received a PhD application from her over the weekend! I cannot emphasize enough what an exceptional scientist she is - I think that any lab would be lucky to have her join.

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Additionally, we think that PAC-1 could have significant utility as part of a broader combination-therapy regimen, to delay or reverse MDR1 activation and enhance tumor sensitivity to SOC chemotherapies.

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Excitingly, PAC-1 has entered clinical testing, where it has been well-tolerated and resulted in multiple patient responses. However, no biomarker capable of predicting sensitive tumors was reported. We think that MDR1 expression could be the missing biomarker.

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How is this possible? We found that PAC-1 is being effluxed by MDR1 - but PAC-1 bound to iron is effluxed much more rapidly than PAC-1 by itself. So, MDR1 activity doesn't protect cells - it accelerates iron starvation in MDR1-high cells by pumping out the drug-iron complex.

We also found that we could use PAC-1 to reverse this process: we took chemo-resistant, MDR1-high cells and cultured them in PAC-1 for a few weeks, and we found that this resulted in a 20-fold decrease in MDR1 expression and a 7-fold increase in chemotherapy sensitivity.

Similarly, evolving cancer cells in chemotherapy causes MDR1 upregulation and resistance to a broad range of anti-cancer. But, these evolved drug-resistant cells exhibited significant collateral sensitivity to PAC-1.

To confirm this association, we generated MDR1-KO clones and we verified that these cells were more sensitive to standard chemotherapies, as we expected. However, we also found that the chemo-resistant MDR1-high cells were much more sensitive to PAC-1 than the MDR1-KO cells!

Surprisingly, using PRISM, we found that the cells most sensitive to PAC-1 were over-expressing MDR1 (also called P-gp). MDR1 stands for MultiDrug Resistance 1: it’s an efflux pump that expels drugs from tumors. But our data suggested that MDR1 conferred PAC-1 sensitivity!

We used the PRISM dataset from @corsellos and found that PAC-1 was behaving like an iron-chelation agent. We confirmed that PAC-1 depleted cellular iron, upregulated an iron-starvation transcriptional response, and PAC-1 lethality could be reversed with iron supplementation.

The drug is called PAC-1. It was initially developed to target cancer cells by activating the executioner caspases. But, we generated CASP3/6/7 triple-knockouts and it still eliminated cancer cells, demonstrating that it must have some other target.

Jason Sheltzer @jsheltzer.bsky.social · 07/09/2025

New from my lab on bioRxiv - we found an existing drug that appears to be safe in humans that selectively kills chemotherapy-resistant cancer cells.

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Very cool! 1) did you make any attempt to eliminate guides likely to cause false-positives due to chromosome truncations? (PMID: 38811841) 2) are you including guides targeting new genes discovered from T2T sequencing, particularly on the sex chromosomes? (PMID: 37612512)

Next up - we want to improve the tumor-specific accumulation of CDK11 to bypass this toxicity, and we’re looking for other emerging drug targets to create mouse models for. If you’re interested in collaborating, feel free to reach out!

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Along the way, we also learned a ton about the biology of CDK11, the 1p36 locus (one of the most frequently-deleted regions across cancer genomes!), and the CDK-dependent control of gene expression.

If you have a mutation that blocks the interaction between your drug and its target, and so long as that mutation is tolerated in mice, then you can do the same thing that we did - make a mouse with the resistance mutation and see what happens after drug treatment.

I think that this approach can substantially improve the drug development process. Nearly all cancer drugs fail during clinical testing, and toxicity is one of the most common reasons why. We urgently need better approaches to predict and study toxicity in a preclinical setting.

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We injected the G568S mice with a mouse cancer cell line and then treated them with a high dose of MEL-495R (which was tolerable to the G568S mice but toxic to WT mice). This resulted in a significant anti-cancer effect, verifying that on-target toxicity limits effective dosing.

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This suggested that toxicity (which we believed to be CDK11-dependent) was limiting our ability to effectively dose these mice. To verify this, we returned to our CDK11-G568S mouse strain to tease apart the cause.

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This gave us confidence to move forward with the drug. We identified a non-toxic dose of MEL-495R and tested it in several xenografts. However, it showed very little anti-cancer activity. A splicing qPCR indicated that this non-toxic dose wasn’t appreciably inhibiting CDK11.

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We bred a large cohort of CDK11-mutant (G568S) and CDK11-WT mice, treated them with an ultra-high dose of MEL-495R, and it worked beautifully. The wild-type mice became very sick while the CDK11-G568S mice were totally fine. Our drug is specific for CDK11 - in living mice!

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We thought - if the mice expressing this mutation are still affected by our CDK11 inhibitor, then that tells us that it’s causing CDK11-independent toxicity. In contrast, if these mice are resistant to the drug, then any side effects of the drug in WT mice are due to CDK11.

We came up with a way to answer this question. We had discovered a mutation in CDK11 that blocks drug binding to it. We thought - what if we put that mutation into a mouse? So, we found the mouse ortholog of the human mutation, CRISPR’d it into some zygotes, and did exactly that.

You can throw every biochemical assay in existence against a drug, but that won’t do it - we can’t test all ~20,000 human proteins at once, it’s really hard to determine drug concentrations in each tissue, and in vivo drug metabolism can generate dozens of derivative compounds.

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This brought us to an issue that is absolutely crucial for cancer drug development. All cancer drugs have at least some toxicity. If you have a drug against a new target (like CDK11), how do you know if that toxicity is due to CDK11 inhibition or due to something else?

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Now, we wanted to take the drug in vivo. Unfortunately, it had a terrible ADME profile. We worked with the talented chemists at Meliora to develop an improved CDK11 inhibitor, and we created MEL-495R, which exhibits potent CDK11 inhibition and superior PK properties.

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Next, we figured out why - 1p36 is where CDK11 and its activating cyclin (cyclin L) are encoded. Having a lower dosage of these genes enhances the dependency on the remaining enzyme, creating a synthetic-lethal relationship.

For any cancer therapy, finding a biomarker to predict sensitivity is key. We analyzed screening data with CDK11-targeting CRISPR, CDK11-targeting RNAi, and OTS964 treatment, and they all pointed to the same biomarker: Chr1p36 deletions enhance sensitivity to CDK11 ablation.

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Next, we uncovered the cell biology of CDK11 inhibition. We found that CDK11 controls gene expression through two distinct mechanisms: ensuring accurate splicing via SF3B1, and, separately, controlling the transcription of certain genes by promoting the activation of RNAPII.

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First, we did the fundamental molecular genetics: targeting CDK11 with OTS964 or CRISPR killed cancer cells, and this could be rescued with a mutation in CDK11 that blocked drug binding or with gRNA-resistant cDNA (but not if the cDNA contained a kinase-inactivating substitution).

CDK11 is a member of the cyclin-dependent kinase family. Other CDK inhibitors, like the CDK4/6 inhibitor palbociclib, have revolutionized the treatment of certain cancer subtypes. So, we set out to characterize CDK11 as a possible therapeutic vulnerability in cancer.

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One of these mischaracterized drugs is called OTS964. While it was initially developed as a PBK inhibitor, we showed that it actually functions by inhibiting CDK11 - making it the first-ever inhibitor of this poorly-characterized kinase.

Thrilled to share our new paper describing the development and characterization of CDK11 inhibitors for cancer therapy. We also establish a new system that I think represents a huge leap forward in our ability to understand drug toxicity in a living organism.

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At Stanford, I’ll be affiliated with the Stanford Cancer Institute, Radiation Oncology, and Pathology. My lab will be in the Research Park complex on Page Mill Road. I’m looking forward to getting to know my new community! Feel free to reach out and say hi.

As some of you may know, my wife Joan has been leading AI infrastructure engineering at Google. I’m grateful that we have the chance to relocate to the Bay Area, which offers so many phenomenal opportunities in tech, biotech, and biomedical research.

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I’ve had a terrific experience at Yale, and I’m sad to be leaving an amazing group of collaborators and friends. Yale has created a cutting-edge environment for translational cancer research and I’m thankful for all of the things that I’ve been able to learn here.

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Jason Sheltzer @jsheltzer.bsky.social · 23/05/2025

I’m thrilled to share that I’m joining the faculty at the Stanford University School of Medicine. My lab and I will be relocating to Stanford this summer!

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If you're an international PhD student at Harvard working on something that my lab is familiar with and you're at risk of deportation, shoot me an email. We may be able to host you or find someone else who can.

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Jason Sheltzer @jsheltzer.bsky.social · 09/05/2025

The VC firm Lux Capital has launched a new $100M program to help scientists whose funding has been cut. Looks amazing - and I hope that more venture firms and philanthropies will follow their lead. www.luxcapital.com/news/our-hel...

luxcapital.com

Our Helpline for American Scientists

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Jason Sheltzer @jsheltzer.bsky.social · 05/04/2025

The 2025 Breakthrough Prize in Life Sciences was awarded to: Drucker, Habener, Holst, Knudsen, and Mojsov for GLP-1/ozempic, Hauser and Ascherio for treating multiple sclerosis, and David Liu for CRISPR base editing. Terrific choices! breakthroughprize.org/News/91

breakthroughprize.org

Breakthrough Prize – Breakthrough Prize Announces 2025 Laureates in Life Sciences, Fundamental Physics, and Mathematics

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Jason Sheltzer @jsheltzer.bsky.social · 04/03/2025

For the first time since January, notification of a new NIH study section meeting has been posted on the Federal Register. It seems to cover multiple review panels, including one for the DP2/New Innovator grant. www.federalregister.gov/agencies/nat...

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It’s a prime example of how public investment in research yields life-saving treatments, and many - including President Trump - benefit from this history.

In the end, statin development owes a huge debt to NIH-funded science. NIH-backed research identified high cholesterol as a major disease risk, discovered how to reduce it, and provided critical evidence that saved statin development when industry faltered.

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Bolstered by these findings, Merck revived its statin program and launched large-scale trials that proved that statins safely lowered the risk of heart attacks. In 1987, lovastatin earned FDA approval, launching a new era in heart disease prevention. pmc.ncbi.nlm.nih.gov/articles/PMC...

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Outside of pharma, NIH-funded researchers continued to evaluate statins. Brown and Goldstein showed that it safely lowered cholesterol in dogs, and others showed that it produced positive results in patients with abnormally high cholesterol levels. pubmed.ncbi.nlm.nih.gov/6262757/

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A historical perspective on the discovery of statins

In 1980, Merck initiated the first clinical trials using an HMG-CoA reductase inhibitor, called lovastatin. But the initial trials were halted over safety concerns - potentially ending statin’s commercial development. pmc.ncbi.nlm.nih.gov/articles/PMC...

pmc.ncbi.nlm.nih.gov

Cholesterol is essential for the functioning of all human organs, but it is nevertheless the cause of coronary heart disease. Over the course of nearly a century of investigation, scientists have deve...