June 8, 2020

Fasting

#114 – Eileen White, Ph.D.: Autophagy, fasting, and promising new cancer therapies

"I would like to translate what we've learned about the role of autophagy in cancer and that involves developing small molecules to inhibit autophagy for cancer therapy." — Eileen White

Read Time 28 minutes

In this episode, Eileen White, Chief Scientific Officer at the Rutgers Cancer Institute, describes the fundamental role of autophagy in the maintenance of health and prevention of neurodegeneration, cancer, and other diseases. She also goes into detail about the paradoxical finding that autophagy may benefit an existing cancer cell and help it to survive—a discovery leading to new possibilities in cancer therapy. We also discuss fasting (and molecules that induce autophagy) and the critical need to decode the proper fasting “dose” in order to improve human health.

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We discuss:

  • Eileen’s discovery that a specific oncogene blocks apoptosis [3:40];
  • Defining apoptosis and its role in cancer prevention [10:00];
  • How cancer cells use the autophagy pathway to survive [17:20];
  • Stressors that induce autophagy [29:15];
  • The importance of autophagy in the brain and liver [32:45];
  • The mechanisms that can trigger autophagy to support longevity [40:00];
  • Evidence for cancer treatment by blocking autophagy [42:30];
  • Types of cancer that are most autophagy-dependent [46:45];
  • The autophagy paradox [52:40];
  • Finding a molecular signal for autophagy [59:15];
  • Current knowledge gaps around fasting as a tool for longevity [1:13:00];
  • Rapamycin, metformin, and other molecules that may induce autophagy [1:22:15];
  • How to study fasting and exercise as longevity tools [1:32:50];
  • The Nobel Prize for autophagic research [1:36:45];
  • Eileen’s future areas of research [1:38:25];
  • A fasting strategy for Alzheimer’s disease prevention[1:49:25];
  • Future study of metabolism and autophagy [1:51:30]; and
  • More.

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Eileen’s discovery that a certain oncogene worked by blocking apoptosis [3:40]

When she got interested in science?

  • Eileen’s parents fostered her interested in scientific discovery
  • Eileen got a PhD in biology
  • She studied in the department led by Dr. Arnie Levine, who discovered p53 
  • She then went to Cold Spring Harbor Lab where she got a postdoc with Bruce Stillman
  • There were two Nobel Prizes awarded while she was there
  • She then went to Rutgers to be on the faculty
  • Shortly after that, they hired a cancer center director, Bill Hait, and she and Bill helped to build what’s now the Rutgers Cancer Institute

So where in your journey did autophagy peak your curiosity?

  • She was given an oncogene to study while a postdoc 
  • She found that this gene was a viral homolog of Bcl-2
  • Bcl-2 is a human oncogene and it functions by blocking apoptosis (programmed cell death)
  • So she figured out that one novel function of cancer is to evade cell death
  • Then the pharmaceutical industry started developing inhibitors of Bcl-2 to promote apoptosis in cancer
  • That was the “ultimate goal”… to make tumor cells die and have a drug that will do that
  • Eileen’s lab is still involved with taking those drugs and putting them in patients and optimizing their use in solid tumors

 

Defining apoptosis and its role in cancer prevention [10:00]

How apoptosis works

  • Family of proteins called the Bcl-2 family
    • Some of the Bcl-2 like proteins (e.g., Bcl-xL) inhibit apoptosis so they keep tumor cells alive
    • BH3 only proteinsantagonizers of Bcl-2 proteins and they are often activated to inhibit Bcl-2 to trigger apoptosis via the initiation Bax/Bak-dependent apoptosis
    • BAX and Bak ⇒ the core apoptotic machinery that triggers apoptosis
      • They reside in the mitochondrial membrane
      • When they’re triggered to undergo apoptosis, they oligomerize and poke holes in the mitochondrial outer membrane and that releases proteins that activate proteases to grade the cell 
        • Bcl-xL, for example, and other inhibitors of apoptosis, are trying to antagonize this process

What goes wrong in a cell for it to go down the suicidal pathway?

    • Mitochondrial damage can certainly trigger apoptosis
    • But the best way to explain it is by using the example of p53
      • p53 is a tumor suppressor and one of the functions is to promote apoptosis to prevent an emerging cancer cell from progressing
      • One mechanism by which p53 does that is by turning on the transcription of PUMA and Noxa (antagonizers of Bcl-2 and activators of Bax and Bak) 

 

  • What activates p53 to do that?  

 

      • That could be a long list of things from DNA damage, oxidative stress, and more
    • In summary, something bad happens to an emerging cancer cell and then p53 gets activated and one of the tumor suppression functions of p53 is to turn on these promoters of apoptosis that antagonize Bcl-2

Mutations in p53 accounts for about half of all cancers

  • Hotspot mutations in p53 that are very common in cancer 
  • p53 functions as a heterodimer
  • What these mutant p53s do is that they end up entering into a dimer with wild type subunits and that interferes with the function of the complex
  • It can be a loss of function of the p53 heterodimer
  • But there’s evidence that it not only causes a loss of function, but it actually may do other things as well that are cancer-promoting

What happens post apoptosis?

{end of show notes preview}

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Eileen White, Ph.D.

Dr. Eileen White, Ph.D. is the Chief Scientific Officer and Deputy Director for Basic Science at the Rutgers Cancer Institute of New Jersey, an NCI-designated Comprehensive Cancer Center. She is also a Distinguished Professor of Molecular Biology and Biochemistry at Rutgers University. Dr. White currently serves on the Board of Scientific Advisors for the National Cancer Institute.

Current research of the White Laboratory at the Rutgers Cancer Institute of New Jersey is focused on determining the role of the catabolic process of autophagy in protein and organelle homeostasis, and how this recycling of cellular components sustains cancer metabolism and tumorigenesis.

She is the recipient of numerous awards including a MERIT award from the National Cancer Institute, the Red Smith award from the Damon Runyon Cancer Research Foundation, a Howard Hughes Medical Institute Investigatorship, an Achievement Award from the International Cell Death Society, a Career Award for the European Cell Death Organization, and is an elected Fellow of the American Society of Microbiology (ASM) and the American Association for the Advancement of Science (AAAS).

She is currently on the External Advisory Boards of the Yale, Case, and MGH Comprehensive Cancer Centers and her Editorial Board memberships have included Genes & Development, Cancer Discovery, the Journal of Cell Biology, Oncogene, Cancer Prevention Research, Molecular Cancer Research, Autophagy and Cell Death and Disease. [vescortx.com]

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  1. Agree very much that a bigger focus on prevention would have a much better cost benefit outcome.

    As well as fasting and exercise being the low hanging fruit re chronic diseases, would also add diet. After all the very large Global Burden of Disease study (2017) lists lack of whole grains and fruit as major problems as below:

    “In 2017, 11 million (95% uncertainty interval [UI]) deaths and 255 million (234–274) DALYs were attributable to dietary risk factors. High intake of sodium (3 million deaths and 70 million DALYs), low intake of whole grains (3 million deaths and 82 million DALYs), and low intake of fruits (2 million deaths and 65 million DALYs) were the leading dietary risk factors for deaths and DALYs globally and in many countries”

    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30041-8/fulltext#seccestitle160

    • I chuckle over the fact that moments ago I told my cellphone averse sister: “Blog? — Don’t blog” and yet here am I… With what appears to be a swifly growing breast tumer .subsequent

  2. Hi Peter
    Another very thorough interview. I was intrigued by the discussion of doing the trials to define dose recommendations for diet/fasting and exercise in a rigorous way. Given the huge incidence of lifestyle driven non-communicable disease it seems clear that in human health terms no other research could provide that kind of payoff. My personal focus is NAFLD/NASH/cirrhosis but it is all foundationally lifestyle driven. I was wondering if a non-profit might be able to champion that research and actually bring the tools you talked about together to do that research? I’m CEO of the Fatty Liver Foundation and my members die every day from these metabolic problems but the only tools we have are pretty crude.
    Wayne

  3. On the one hand, fasting up regulates autophagy, which may prevent cancer. On the other, certain cancers use autophagy to survive. Many cancers are thought to have been present and growing for years without the host’s knowledge, before diagnosis. In the absence of a clear dividing line between cancer prevention and “oops – it’s too late,” it sounds like my diligent fasting protocols could be having unintended consequences. I hope Peter will say more about this at some point. It’s one thing to attempt to harmonize the data, as he did, and another to translate that into something actionable in “real life.”
    Thank you for another excellent discussion.

  4. I tend to think that the nutrient deprivation that comes with fasting would offset any benefit cancer cells got through the additional upregulation of autophagy as a result of fasting. Certainly if you’re pursuing a cancer cell into a greater autophagic state, at the very least, you’re pumping the brakes on it’s growth by stressing its very survival.

  5. Peter,
    It Is still very surprising to me that Prof. Longo has not been in your show yet! If I remember well, he originally planned to fast patience for 10 days of water fasting. That is the original Longo protocol. But no one wanted to do it nor support it. That is why he reduced the time to 5 days (mon-fri) and added a bit of food (fmd). If any white robe person has a clue about dosage, he is the one. It would be fantastic if you can schedule a conversation with him!

    Also, remember that white robe people did not develop fasting therapy. And also these therapies were not developed in the past 100 years. So, it would be nice to trust the original developers and take a look to Indian fasting therapies (or others) to figure out the right length. You do not have to reinvent the wheel of fasting.

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