Thanks Caroline! 🙏

Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors Diet can impact anticancer drug activity. A classic example in rodents is a ketogenic diet enhancing PI3K inhibitor activity. Here, we show that phytochemicals and their microbiome derivatives, rather than macronutrient composition, underlie this phenomenon.

Now online! Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors

20/ Thanks for reading this far! I hope you’ll check out the full story in the paper.

19/ Grateful to our funding sources, including @ludwigcancer.bsky.social, @su2c.bsky.social, and NJCCR.

18/ Thanks also to the anonymous reviewers, the @cellpress.bsky.social editorial team, and Deputy Editor @snarasimhan.bsky.social for their thoughtful input and support during the revision process.

17/ This work would not have been possible without fantastic collaborations with the Donia lab (Sunghoon Hwang, Sophia Koval) the Kang lab (Qianying Zuo) and Jessie Guo’s lab!

16/ I'd like to thank Josh for his incredible mentorship throughout the project, and all the Rabinowitz lab members for their support—including: ‪Wenyun Lu, Ricardo Cordova, Mike MacArthur, Jacob Boyer, @sarahmitchellphd.bsky.social, Craig Hunter, Rolf-Peter Ryseck, Jenna AbuSalim and more.

15/ Further research is needed to understand how these findings translate to humans. Nevertheless, they highlight the importance of considering diet and microbiota when evaluating drug exposure, preclinical efficacy, and inter-individual variability in therapeutic response.

14/ Using bioassay-guided fractionations we identified the key soy phytochemicals responsible: soyasaponins (SSA), which are transformed into soyasapogenols by the gut microbiome. Soyasapogenols activate liver CYP, leading to reduced PI3Ki exposure and loss of tumor control.

13/ We found it was soy, which is abundant in standard rodent chow! It wasn’t the soy protein, but rather the small molecules—phytochemicals—in soy that activated liver CYP in a microbiome-dependent manner.

12/ Next, we asked: what ingredient in chow is responsible for activating drug clearance, leading to the reduced efficacy in chow-fed mice?

11/ The increased drug exposure wasn’t due to suppression of direct drug metabolism by the gut microbiota, but rather to reduced hepatic CYP450-mediated clearance.

10/ We then discovered that the effect was mediated by drug pharmacokinetics—drug exposure was higher in mice fed purified diets or treated with antibiotics.

9/ After we were convinced the results were real and robust, we set out to investigate the mechanism. First, we found that antibiotics that ablate the microbiome also strongly enhance the anticancer activity of the drugs.

8/ To test whether the control diet was the real driver, we ran the experiment shown in the first figure panels of the paper—directly comparing the two high-carb control diets (plus keto). The results were clear: the “secret sauce” boosting PI3Ki efficacy was switching to a purified diet!

a man in a suit is sitting in a chair with the words `` control ! control ! control . '' ALT: a man in a suit is sitting in a chair with the words `` control ! control ! control . ''

7/ But after more thought we realized the difference between our experiment and the previous—the key was the control diet used! While we used a control purified diet (which, like keto, is made of refined ingredients)—the previous study used a standard grain-based chow as control.

6/ At this point, I remember coming to the lab complaining that I got these strange results and that my experiment had probably failed :/

a close up of a man with his mouth open . ALT: a close up of a man with his mouth open .

5/ We tested how varying protein levels in ketogenic and high-carb diets affect the anticancer efficacy of PI3Ki in mice. As expected, the drugs worked well on the keto diet. But surprisingly, PI3Ki showed similarly strong efficacy on the high-carb control diet too!

a south park cartoon shows a man and a woman talking about the odds ALT: a south park cartoon shows a man and a woman talking about the odds

4/ As sometimes happens in science, this project began with a serendipitous result I observed at the end of my first postdoctoral year ->

Suppression of insulin feedback enhances the efficacy of PI3K inhibitors - Nature Glucose–insulin feedback can reactivate PI3K in tumours treated with PI3K inhibitors, reducing therapeutic efficacy, but this effect can be reduced by using drugs or diet to suppress the insulin respo...

3/ This project builds on the beautiful work by the Cantley lab, which showed that low-carbohydrate ketogenic diet dramatically enhances PI3K inhibitor (PI3Ki) efficacy in murine cancer models. www.nature.com/articles/s41...

Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors Diet can impact anticancer drug activity. A classic example in rodents is a ketogenic diet enhancing PI3K inhibitor activity. Here, we show that phytochemicals and their microbiome derivatives, rather...

Link to the paper: www.cell.com/cell/fulltex...

Thrilled to share that my main postdoctoral project in Josh Rabinowitz’s lab is out today at @cp-cell.bsky.social ! We found an unexpected, diet- and microbiota-dependent mechanism that affects the anticancer activity of PI3K inhibitors. Thread below 👇

Lack of consistent effect of dietary fiber on immune checkpoint blockade efficacy across diverse murine tumor models Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain low in most cancers. Recent research suggest that dietary fiber enhances ICB response in melanoma patients a...

Happy to share our effort to better understand how dietary fiber impacts metabolite levels and cancer immunotherapy
www.biorxiv.org/content/10.1...

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Join me and leading Israeli researchers & postdocs worldwide as we explore cutting-edge science and breakthroughs. Don’t miss this online event—register now!
www.scienceabroad.org.il/life-science...
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