PodcastCancer

# Science Signaling Podcast for 14 March 2017: The Cancer Moonshot

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaan1418
DOI: 10.1126/scisignal.aan1418

## Abstract

This Podcast features a conversation with Science Signaling’s Chief Scientific Editor Michael Yaffe about opportunities for signaling researchers to contribute to the Cancer Moonshot, a federally funded initiative to accelerate cancer research. Administered by the National Cancer Institute (NCI), the goal of the program is to improve the prevention, diagnosis, and treatment of cancer. Signaling pathways are not only critical for the initiation and progression of cancer; they are also critical targets for treatment. In addition to developing new therapies, there are many other opportunities for signaling researchers to advance the goals of the Cancer Moonshot, such as improving methods of diagnosis and prevention.

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Length: 16 min; file size: 11.5 MB; file format: mp3

## Transcript

Host – Annalisa VanHookWelcome to the Science Signaling Podcast for March 14th, 2017. I'm Annalisa VanHook, and today I’m talking with our Chief Scientific Editor, Michael Yaffe, about the Cancer Moonshot initiative.

About a year ago, Vice President Joe Biden launched an initiative called the Cancer Moonshot to increase federal funding for cancer research. In December, the US Senate approved a bill called 21st Century Cures that will channel $6.3 billion over 10 years into the discovery, development, and implementation of new treatments for many diseases.$1.8 billion of this funding is specifically earmarked for the Cancer Moonshot initiative, which is administered by the National Cancer Institute and will be used over the next seven years to fund cancer research, drug development, and clinical trials. Some grants have already been awarded from this funding, and applications for many more funding opportunities are now being accepted or will begin accepting submissions in the near future.

Today I’m talking to Science Signaling's Chief Scientific Editor, Michael Yaffe, about the opportunities that this new funding offers, and how he thinks that these increased efforts can best serve the goals of identifying, developing, and implementing new cancer treatments.

Interviewer – Annalisa VanHookHi, Michael, welcome to the Science Signaling Podcast.

Interviewee – Michael YaffeThank you very much, Annalisa.

Interviewer – Annalisa VanHookSignaling pathways are at the heart of cancer. Dysregulation of signaling pathways that control cell proliferation and death drive the proliferation of cancer cells and help them evade destruction by the immune system. Pathways that control cell metabolism affect how cancer cells acquire and use energy. Pathways that control cell migration are involved in metastasis. And beyond the cancer cells themselves, signaling pathways also control how the immune system responds to cancer cells and how neighboring normal cells interact with tumor cells. How has our extensive characterization of genomic alterations in cancer cells changed how we think about signaling in cancer cells?

Interviewee – Michael YaffeI think one of the main take-away messages that's come from this vast expanse of genomic data has been the surprising finding that many of the mutations that we think are driving the cancer turn out to be in signaling pathways that we have already understood. It's been a bit of a surprise to me the relative sparsity of new driver genes that have emerged in studying many of these tumor types. This is good news for those of us in signaling because it says that the things that we've been studying for so long are truly the right things to be studying, and it suggests that the pathways whose molecular dissection we have devoted so many years to are likely now to be excellent therapeutic targets for the treatment of various types of cancers. Maybe the other thing that's really important is the recognition that of the relatively small number of pathways, the dependencies of different tumors on certain pathways is different.

Interviewer – Annalisa VanHookEven in the sorts of cases where you can identify a specific mutation that initiated the transformation of normal cells into cancer cells, by the time that cancer has grown—and by the time that cancer is diagnosed—the tumor cells have undergone a lot of rewiring in terms of signaling pathways and metabolic pathways that can't be detected by genomic analysis. So a lot of the factors that are driving the tumor cells and the cancer progression are not reflected in the DNA.

Interviewee – Michael YaffeYes, we are rapidly moving to the post-genomic age. I think that one of the things that has been very clear when we look at the emergence of tumor resistance, which by the way is one of the areas that the Blue Ribbon Panel's recommendation areas for focus in cancer therapy are, has been the finding that in many cases resistance arises from the rewiring of signaling pathways that would be difficult to predict looking at the genomic data alone. Instead, the rewiring seems to be occurring at the level of signaling pathways.

What this means is that we will have to follow another of the Blue Ribbon Panel’s recommendations and find alternative technologies in order to decipher how the information is flowing when these pathways are rewired and come up with new types of signatures that tell us about this signaling pathway rewiring in the absence of identifiable genomic changes.

Interviewer – Annalisa VanHookYou mentioned the Blue Ribbon Panel. That's a panel that the NCI convened last year—a panel of experts—to give recommendations about how the Cancer Moonshot funding should be used. What were those recommendations?

Interviewee – Michael YaffeYou can break the recommendations down into two groups. One group has to do with the manner in which we do the science and the manner in which we engage cancer patients. And so, several of the recommendations involved establishing networks for patient involvement and trying to come up with better ways to share the data on patients. A second part of the recommendations had to do with what we should be focusing on. For example, intensifying research on childhood cancers, where it's likely that the drivers responsible might be monoallelic. And then, the third group of recommendations had to do with what specific areas to focus in, particularly immunotherapy and the development of new technologies.

Frankly, I was a little disappointed that there wasn't more of an emphasis on moving beyond genomics and beginning to examine alterations in the proteins themselves, the manner in which these proteins are connected and the manner in which these connections—which would not be revealed by genomic analysis alone—are responsible for development, progression, and resistance of the disease to treatment. I hope that as the NCI moves forward to implement many of the recommendations of the Blue Ribbon Panel that they will keep in mind that signaling research has not only revealed the biological mechanisms by which these tumors arise, but that the vast majority of small molecule agents and antibodies that are currently used in cancer treatment are focused on these signaling pathways rather than the genetic mutations themselves.

Interviewer – Annalisa VanHookGene therapy is clearly a possibility for monogenic diseases, diseases that are caused by a single mutation or a couple of mutations. But, in cancer cells, even if you could identify the single most important mutation that initiated the transformation of normal cells into cancer cells, replacing that gene after the fact—after the cells have become transformed—isn't necessarily going to fix the problem because the cells have already undergone all the rewiring that's needed to maintain their growth.

Interviewee – Michael YaffeI think there are a few ways that one could potentially use gene therapy to treat cancer, particularly if one were to engineer, for example, the immune system. But I think the cancer cells, trying to genetically engineer alterations in the cancers cells, well, the horse has already left the barn. There's no point in trying to focus on that.

Interviewer – Annalisa VanHookHow do you think that signaling researchers can use these new funding opportunities to be the most effective in getting new treatments identified and into the clinic?

Interviewee – Michael YaffeLet me give you four suggestions. One thing that we could focus on would be pathway redundancy and rescue. And these are kind of non-obvious things. For example, the reactivation of a pathway that has been silenced by a particular drug. Consider, for example, the intense interest in administering both BRAF inhibitors and MEK inhibitors as combination therapy, which works wonderfully in certain instances of melanoma to prevent the emergence of resistant disease. Now, importantly, this is the exact opposite of the conclusion that one would draw if you thought about cancer purely as a genomic disease. Because, for example, a null allele of BRAF when combined with a null allele of MEK would have no net effect, right? That these are in the same pathway, and therefore they're epistatic with respect to one another. But, in the setting of complex signaling pathways where silencing of BRAF still can lead downstream to reactivation of MEK through another pathway, this type of understanding and targeting of pathway redundancy may have real therapeutic benefit.

I think along those same lines a second approach that people could take is to look at pathway-to-pathway dependencies. Can we find synthetic lethality at the signaling level. When we block one signaling pathway, do we now make the cells more dependent on a second signaling pathway that we could target by the coadministration of combination chemotherapies? I think a third area that has not been quite as well explored, although it has been partially explored, would be targeting protein homeostasis—making agents that target protein degradation or the unfolded protein response. And these are covered in the current issue of Science Signaling.

In addition, one might begin to think about using signaling signatures as diagnostics rather than mutational signatures. We would have to develop new technologies in order to be able to implement them. And at the moment, technologies like mass spectrometry, while wonderful in the laboratory, have not yet risen to the level where we see them routinely applied to clinical cases. However, wouldn't it be wonderful if in the future we could take some type of biopsy and immediately get feedback on the activation status of a handful of critical pathways that we know are important in tumor progression? The MAP kinase pathway, the PI3 kinase pathway, the NF-κB pathway, and so forth.

And, finally, maybe it's worth thinking about signaling heterogeneity in the context of tumor heterogeneity. It's clear now that there's tremendous tumor heterogeneity at the genomic level. But there's undoubtedly also significant tumor heterogeneity at the signaling level. And perhaps if we had a better idea of the extent to which that heterogeneity contributes to the development of resistant disease, we could come up with novel therapies in order to prevent tumor resistance and enhance chemosensitization.

Interviewer – Annalisa VanHookWere there any other recommendations from the Blue Ribbon Panel that might prompt signaling researchers to think outside of the box?

Interviewee – Michael YaffeI think there are two areas that the Blue Ribbon Panel focused on which we, as signalers, have not traditionally addressed. One of those is minimizing cancer treatments’ debilitating side effects. I think that when we've been focusing on understanding signaling pathways we've really been focusing on what's happening in the tumor cell and how we can optimize our therapies in order to alter those signaling pathways. But clearly, it's also the activation of signaling pathways in the adjacent normal cells that contribute to the toxic effects of therapy. And perhaps, as signalers, we should also be looking not only at the effects of our treatment on tumors, but we could pursue the signaling changes that happen in adjacent normal tissues and how those are influenced not only by the therapy but by the response of the tumor itself and how that affects the surrounding tissue microenvironment.

A second area in which the Blue Ribbon Panel made some suggestions was expanding the use of proven cancer prevention in early detection strategies. I think that the role of signaling in cancer prevention has been significantly understudied and underappreciated, and this is another area in which signaling researchers could likely contribute. Clearly this would involve crosstalk between people that think about traditional signaling and people who think about DNA damage and epigenetic changes that contribute to alterations in gene expression, all of which over time we think ultimately culminate in adult cancer. In contrast to pediatric cancers, where it seems far more likely that a single or small number of mutations is sufficient to initiate and drive the disease.

Perhaps we could identify different populations of people in which one signaling pathway is more dominant over another and vice versa. And perhaps it's those nongenomic alterations and stochastic fluctuations that underlie why some populations are predisposed to certain types of tumors or certain types of illnesses. I think that examining the heterogeneity in signaling pathway status within different populations of people might be another way to get at cancer prevention or cancer risk.

Interviewer – Annalisa VanHookThere are many examples of mutations that confer increased risk of developing a certain type of cancer, but certainly not everyone who has that mutation develops the cancer. So, understanding underlying differences between individuals—specifically in signaling pathways—might help us understand why some people with the mutation develop the disease, and some people don't.

Interviewee – Michael YaffeIt may be that we don't have to take an antagonistic view to these genomic mutations in genetic studies, and instead perhaps it's the interplay between the mutational background on one hand and the signaling environment on the other that controls the emergence or failure of emergence of a particular tumor type in a particular individual.

Interviewer – Annalisa VanHookDid the Blue Ribbon Panel have any recommendations for—or is there any increased interest in—revisiting some of the cancer drugs that we already use and that are rather effective but might have some rather nasty side effects, some unintended consequences of using the drug?

Interviewee – Michael YaffeAn excellent question, and there were two suggestions from the Blue Ribbon Panel related to that. One was a specific emphasis on minimizing cancer treatments’ debilitating side effects, and that focuses not just on the side effects in the vicinity of the tumor, but this refers to side effects on all the tissues of the body that might be affected by the cancer therapies. And clearly, there's a big interest in trying to minimize toxicity while we try to increase efficacy. At the same time, as we learn how to manipulate these side effects, it may be possible to re-explore old drugs that have been around for a long time but that are no longer used because of their disparaging side effects. Perhaps as we understand—by studying normal tissues—how a particular therapy leads to these side effects, we might be able to come up with inhibitors that don't necessarily act on the tumor cell but act to inhibit the toxicity of the drug on the normal cell.

Interviewer – Annalisa VanHookThanks, Michael, for talking with me.

Interviewee – Michael YaffeMy pleasure, Annalisa.

Host – Annalisa VanHookThat was Science Signaling Chief Scientific Editor, Michael Yaffe. This week’s issue of Science Signaling focuses on cancer, specifically on the proteins that contribute to the development and progression of cancer (1). This issue includes three reviews, and those focus on the protein degradation system in cancer (2), ER stress and the unfolded protein response in glioma (3), and the molecular signatures of pediatric brain tumors (4). The issue also includes new research on a protein that's both a diagnostic marker and a driver of prostate cancer (5) and on proteins that drive melanoma (6).

For more information on the Cancer Moonshot, go to the National Cancer Institute’s website at www.cancer.gov and navigate to the section on Research, which includes links to all of NCI’s key initiatives. Or you can go directly to the Cancer Moonshot website at www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative.

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The Science Signaling Podcast is a production of Science Signaling and the American Association for the Advancement of Science—Advancing Science, Serving Society. If you have any comments or questions, you can write to us at sciencesignalingeditors{at}aaas.org. I'm Annalisa VanHook. On behalf of Science Signaling and AAAS, thanks for listening.

## Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Biochemistry, biotechnology, cell biology, genetics and heredity, human biology, molecular biology, pathology, pharmacology

Keywords: Science Signaling, Cancer Moonshot, federal funding, research grants, National Cancer Institute, National Institutes of Health, NCI, NIH

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