3 Questions on…
Answers straight from the experts on the latest news and topics in oncology

Friday, February 10, 2017

With John P. O'Bryan, PhD, of University of Illinois College of Medicine

By Sarah DiGiulio

The RAS family of proteins is an attractive one—as far as cancer biologists are concerned. Mutations for genes in the RAS family are found in nearly 30 percent of all cancers. And they're highly prevalent in some of the most common cancers including colon, lung, and pancreatic cancer, as well as melanoma. Discovering or creating a drug to target RAS would be a big deal.

Now a group of researchers at the University of Illinois at Chicago say a new synthetic binding protein they created in the lab may put them one step toward that goal.

"Developing a RAS inhibitor has been the holy grail of cancer biology," noted John P. O'Bryan, PhD, Associate Professor of Pharmacology in the University of Illinois College of Medicine. "We did not look for a drug or specifically for an inhibitor," O'Bryan said about the new study from he and his colleagues.

"We used monobody technology, a type of protein-engineering technology, to identify regions of RAS that are critical for its function."

In an interview with Oncology Times, O'Bryan further explained why his group decided to investigate monobodies and how they interact with RAS—and why these new findings put translational oncology one step closer to an effective RAS inhibitor.

1. What is new about the findings from this study?

"Our work revealed for the first time the importance of the α4-β6-α5 region of RAS for [RAS] function. Our studies found that an engineered protein called NS1 monobody binds that α4-β6-α5 interface on RAS and actually blocks RAS's oncogenic and signaling ability—which is quite surprising since it didn't seem to interfere with the ability of RAS to interact with its downstream targets. This new area potentially could be used as a way to therapeutically inhibit RAS in the future.

"Also, this work demonstrated for the first time that RAS actually interacts with itself to activate its downstream targets. And that's been a question in the literature for quite a few years now—how RAS activates its downstream targets. This research provides some of the first strong evidence that there is indeed RAS-RAS interaction that is important for activation of downstream effectors."​

2. What is the NS1 monobody and why did you decide to try using it to interfere with RAS instead of looking at another way of interfering with RAS?

"NS1 is a new [monobody]. Monobody techonology was actually developed by our collaborator Dr. Shohei Koide (who was previously at the university and a coauthor on this paper).

"So, monobodies are engineered proteins. They're much smaller than antibodies, which are very difficult to use within cells because of the reducing potential inside a cell. Monobodies in contrast lack disulfide bonds and are, therefore, resistant to the reducing environment of the cell. They're much easier to work with in terms of expressing them in cells and targeting them to your protein of interest. So they're much easier to genetically encode— to use as a way of targeting the pathway of interest, in this case RAS.

"We isolated a monobody that could specifically recognize RAS and it turned out that it actually inhibits RAS signaling and oncogenic activity. Monobodies have been around for a while, but this monobody to RAS is quite new and quite specific—and turned out to be very interesting in its ability to block RAS function."

3. What's the next step—how do you use this research to develop a drug that targets all these cancers with mutated RAS proteins?

"That's the million-dollar question. RAS is mutated in roughly 30 percent of human tumors. So we think it's a very important target for developing drugs that will block its function. RAS has not been a very good target for inhibiting because it's more like a little ball without very deep pockets that inhibitors typically like to sit in. So it's been very challenging to inhibit the protein with small molecules.

"There are RAS inhibitors that have been developed: small molecule inhibitors. But those have not proven very effective clinically. There are others that are being developed that target other areas of the protein. But no one has really targeted an interface at this point. So it raises the question of whether we can actually design novel inhibitors to this region that will block RAS function.

"The strategy that we're taking is to try to use the information that we know from how NS1 binds to RAS to see if we can exploit that for developing small molecules that bind in that same region and may then act as inhibitors to the protein. Such inhibitors would actually be more appealing than NS1 itself because—although [NS1] is small—in terms of a drug it's actually quite large. So it's difficult to deliver sufficient quantities into cells of a patient to inhibit RAS. Whereas if we can develop a small molecule that can more easily penetrate cells of tumors—that would be more likely to work as a therapy.

"In terms of time frame for that, with a little bit of luck, hopefully we'll have some in a few years. But that remains to be seen."

Wednesday, January 25, 2017

With Kirsten Ness, PT, PhD, of St. Jude's Department of Epidemiology and Cancer Control

By Sarah DiGiulio​

Long-term survivors of childhood cancers are living longer today than in years past—but long-term health status among survivors is not necessarily improving. Those are the findings from a new analysis of the Childhood Cancer Survivor Study (CCSS) published online ahead of print in the Annals of Internal Medicine (DOI:10.7326/M16-0742).

"Improved survival following a diagnosis of childhood cancer is one of the success stories of modern medicine," study co-author Kirsten Ness, PT, PhD, Faculty Member in the Department of Epidemiology and Cancer Control at St. Jude Children's Research Hospital, Memphis, Tenn., said in a statement. "Surprisingly, the data from [this] survey show a lack of improvement in perceived health status by childhood cancer survivors over the past 30 years, which serves as an important reminder that cures for cancer do not come without some consequences to patients."

This CCSS report includes data from 14,566 patients between 18 and 48. They were treated for childhood cancers (including both solid tumors and blood cancers) during three time periods: 1970 to 1979, 1980 to 1989, and 1990 to 1999. The results showed that survival rates increased in the cohort of survivors treated between 1990 and 1999 compared to the patients who were treated earlier. But there were higher rates of survivors in the most recent cohort reporting poor general health and anxiety.

Additionally, high-risk behaviors including smoking, heavy drinking, lack of exercise, or poor diet were associated with the cancer survivors who reported poorer health status.

Ness and the study coauthors note the worse health outcomes for the survivors treated most recently could in part be explained by those survivors living longer. But the data also suggest there is a lot of work to do in terms of follow-up care for cancer survivors.

1. Why look at this large cohort of thousands of childhood cancer survivors?

"The study was designed to evaluate late outcomes among survivors of childhood cancer with the goal of providing the foundation for interventions to prevent or remediate adverse health outcomes—and also to guide current therapies to minimize late effects. In the study, cancer survivors treated in the more recent era did not report better health outcomes."

2. Several studies have looked at long-term outcomes for survivors of childhood cancers—how are these findings new and/or different? What does this research add to what is currently known about childhood cancer survivors' outcomes?

"These data sets include survivors treated on protocols more similar to the protocols children are treated on today. We expected a lower percentage of survivors would report poor health outcomes—but this was not the case.

"These data sets extend findings from the CCSS into a new decade of survivors. Perceived health outcomes are still a problem for some survivors of pediatric cancers.

"[And] I think that emotional health outcomes are considered less often than others.

"We did report our findings by diagnostic groups here, [but] additional exploration of disease group specific outcomes where we can drill down to specific chronic conditions will be important."

3. What's the next step? What should practicing oncologists—and primary care providers who care for patients who are childhood cancer survivors—know about your findings?

"It is important for health care providers to be aware of some of the perceived health outcomes pediatric cancer survivors are reporting. For survivors, monitoring potential health outcomes is important—early management of pain and emotional health problems, tailored interventions to promote health-optimizing behaviors (diet and exercise), and minimizing risky health behaviors (smoking).

"The good news is the cure is achievable for over 80 percent of children with cancer. Childhood cancer survivors are vulnerable to adverse outcomes in terms of perceived health—they should be monitored and referred for appropriate services to address their needs. Survivors at greatest risk may benefit from intervention."

Tuesday, January 10, 2017

With Carol Weil, JD, in the NCI Cancer Diagnosis Program

By Sarah DiGiulio

The NCI started enrolling patients in the NCI-MATCH trial in August 2015 with the goal of finding better treatments for patients with cancer based on the molecular profiles of their tumors rather than their tumor types. The trial marks a big step for advancing the science of targeted therapies and personalized medicine. But researchers, physicians, and patient advocates all say there is still much work needed to better educate patients about the delivery of such medicine.

"We need to develop best practices around how to communicate suspected germline information to patients who undergo tumor testing—what information patients want and need to know to determine whether to undergo confirmatory germline testing and what patient characteristics are associated with lower or higher levels of stress, anxiety, or depression around the receipt of this information," explained Carol Weil, JD, Program Director of Ethical and Regulatory Affairs in the Cancer Diagnosis Program in the Division of Cancer Treatment & Diagnosis at NCI.

In February 2015, Weil and a committee of oncologists, geneticists, bioethicists, and patient advocates convened to discuss ethical controversies of the trials that would be part of NCI-MATCH. The attendees realized they needed to find better ways to help patients better understand the results of their genetic data that was part of the trial.

"More empirical data were needed to understand both patient and physician attitudes and preferences about the receipt of genetic findings," Weil said. "We need better understanding of the relative benefits and risks of conveying tumor profiling information to patients."

And that is why the COMmunication and Education in Tumor profiling study (COMET) was created, she said. Weil told Oncology Times more about the specific questions COMET seeks to answer and how it works.

1. What is COMET?

"COMET tests the hypothesis that the knowledge patients gain by completing a self-guided, mobile-friendly, and tiered online genetic education program before getting their tumor test results will be associated with lower levels of testable distress, including anxiety, depression, and cancer worry.

"COMET Step 1 is a randomized controlled trial of a web-based genetic education intervention that will be administered to [one arm of] NCI-MATCH patients prior to receiving their genetic test results from the tumor sequencing required in NCI-MATCH. The other arm will receive 'usual care' (i.e., whatever the treatment center normally discusses with patients undergoing tumor profile testing). COMET Step 1 allows us to address the lack of empirical data regarding patients' experience with genetic testing, and learn how to mitigate the distress many patients carry through the tumor profiling process.

"COMET [also] includes a small pilot remote genetic counseling study known as COMET Step 2. As we continue to incorporate whole genome and whole exome sequencing technologies into oncology clinical trials to match patients with treatments that can potentially target their particular tumor mutations, it will be more and more imperative to ensure the availability of genetic counseling services for those with incidental findings. Particularly in the rural and community hospital setting, sites often do not have sufficient numbers of genetic counselors.

"[This] COMET remote genetic counseling pilot explores the feasibility and preliminary outcomes of providing genetic counseling by telephone to advanced cancer patients in whom a potential or suspected germline mutation is found upon tumor profiling in NCI-MATCH."

2. Is there a current standard of care in terms of educating patients about the results of the genetic tests they receive?

"In terms of a standard for genetic counseling when undergoing tumor profiling—there is not really a standard of care.

"[ASCO] has recommended that patients be counseled in advance of gene panel testing about the possibility of suspected germline findings, but there are not really any developed models for engaging in this complex, and often emotionally charged, communication when there is so much uncertainty about the significance of potential findings."​

3. Why would you say COMET is an important part of the MATCH trial?

"Most NCI-MATCH patients won't actually 'match.' They will undergo tumor testing only to discover there is no actionable mutation in their genomic profile for which there is an investigational therapy available in the NCI-MATCH trial.

"As NCI-MATCH patients typically have advanced and/or recurrent cancer, this news could be devastating. It is our hope that participating in COMET will provide some measure of comfort and empowerment for these cancer patients in that they may have better understanding of their personal and family genetics, and can facilitate communication with family members who could medically benefit from this information.

"Also, COMET will give patient reported outcomes on managing potential germline mutations when cancer patients undergo tumor testing. The results will help us design better policies for communicating individual genetic findings in future clinical trials that address the very real emotions and needs of advanced cancer patients."

Monday, January 2, 2017

​With Paul Mischel, MD, of the Ludwig Institute for Cancer Research San Diego Branch and the University of California, San Diego

In a study published in Cancer Cell, Paul Mischel, MD, and his team worked with colleagues at The Scripps Research Institute to identify a metabolic vulnerability in the incurable brain cancer glioblastoma (GBM) and show how it might be exploited for therapy (2016;30(5):683-93). They found that the cholesterol GBM tumors consume in large amounts is almost exclusively produced by astrocytes and imported by the cancer cells. The researchers described how GBM cells re-engineer existing metabolic pathways to ramp up cholesterol import and retention, and demonstrated that these mechanisms can be undermined by an experimental drug for metabolic disease named LXR-623. This drug accumulates in the mouse brain, and the researchers showed it causes dramatic GBM cell death while sparing non-cancerous cells, including astrocytes. They also report the drug dramatically shrank GBM tumors from human patients that were implanted in mice, significantly prolonging their survival. Mischel told Oncology Times more about the research and how it might suggest a new approach to the development of cancer therapies.

1. What turned your attention to cholesterol import and metabolism as a potential vulnerability of GBM?

"Glioblastoma is one of the most sequenced of human cancers. We know more about the mutations that cause the disease than those, perhaps, of any other cancer, since GBM was the first tumor analyzed by The Cancer Genome Atlas. But, so far, we haven't been able to use that information for the benefit of patients. One reason is that the drugs that target those mutations have a difficult time crossing the blood-brain barrier and hardly make it into the tumor.

"We'd been thinking about this problem and wanted to essentially flip it on its head, approaching it by looking not at the oncogenes themselves but at how oncogenes change the way normal, unmutated enzymes are used by the cell. Cancer cells rely heavily on some of those changes for survival, which is why they're referred to as oncogene-induced co-dependencies. Based on previous observations, we suspected that GBM oncogenes radically alter the way GBM cells take up and use lipids like cholesterol. Further, the tumor's location in the brain would also influence how they process cholesterol. We hypothesized that the GBM cell's metabolic co-dependencies and the tumor's location would together create vulnerabilities very specific to GBM cells and targetable with drugs, or experimental drugs, that can get into the brain."

2. Are there additional oncogene-induced co-dependencies or metabolic vulnerabilities in GBM and other cancers that might be ripe for targeting?

"Yes, I think so. We already have evidence that some transcription factors, though they aren't themselves mutated in any way, are used very differently by tumor cells than by normal cells, creating targetable co-dependencies. Tumor cells also process nutrients for glucose metabolism, lipid metabolism, and protein metabolism in very different ways, and these co-dependencies too may create vulnerabilities. This is probably true for cancers in general.

"Currently, the field tends to focus on targeting oncogene products themselves, and most of them are kinases whose enzymatic activity is blocked by the drugs. But many such drugs have trouble accessing their targets, especially in the brain. Yet there are many other drugs that target other critical enzymes and some are highly brain-penetrant. These could be used to treat cancers that either start in the brain or metastasize to the organ. So this whole idea of targeting those enzymes with drugs that aren't from cancer portfolios or pipelines may represent a very viable strategy, because co-dependencies stem from both the tumor itself and from the micro-environment in which the tumor sits."

3. What are the prospects that this strategy or others like it might be evaluated in clinical trials for GBM?

"There are really two aspects to that. One is access to the drugs themselves for testing, and the other is the design of the clinical trial. As to the first point, part of the message of this paper is that drugs that come from outside the cancer therapy pipeline and even drugs that might have failed in the clinic could turn out to be very useful for cancer patients, including brain cancer patients. As we've shown in this paper, the CNS side effects of an experimental cardiovascular disease drug may actually turn out to be a benefit in brain cancer therapy because it suggests the drug is actually getting in there. This would mean really re-examining and repurposing drugs that have failed in trials for other indications.

"The other aspect is that it's very difficult to design clinical trials for cancers of the brain, since they stratify into a whole bunch of different diseases based on their molecular profiles. One of the fascinating aspects of our recent work is that the metabolic co-dependency we identify seems to be there in the vast majority of GBMs, as well as in cancers that have metastasized to the brain. So this raises the possibility of doing really interesting types of clinical trials—for example, global adaptive clinical trials like the recently announced GBM AGILE trial. In such trials, different therapies and strategies can be tested on patients, and the treatments themselves altered, based on the molecular profiles of tumors and new information. Such approaches, which are also being taken for other cancers, will accelerate the development of innovative therapies like the targeting of cancer cell metabolism and other co-dependencies."

Monday, December 12, 2016

With Yair Lotan, MD, at UT Southwestern Medical Center, Dallas

By Sarah DiGiulio

In May 2012, the U.S. Preventive Services Task Force (USPSTF) issued a grade D recommendation against the use of PSA-based screening for prostate cancer in men of all ages based on data showing that PSA-based screening contributes to overtreatment and over diagnosis of prostate cancer (Ann Intern Med 2012;157:120-134).

That recommendation has sparked controversy since it was first issued. A new study analyzed the real-world data on PSA ordering and referral practices in the years surrounding that recommendation (at UT Southwestern Medical Center) to help understand its effect on practice (Cancer DOI: 10.1002/cncr.30330).

"The United States Preventive Services Task Force recommendation against PSA screening generated significant controversy," noted study author Yair Lotan, MD, Chief of Urologic Oncology and the Helen J. and Robert S. Strauss Professor in Urology at UT Southwestern Medical Center. "We examined a large, whole-institution dataset in the years before and after the USPSTF recommendations reflecting actual practice and found that the changes in PSA use at our institution, if any, were small," he explained. "This is more consistent with behavior seen after the vast majority of practice recommendations."

The researchers included 275,758 male ambulatory care visits between 2010 and 2015 at UT Southwestern Medical Center. The data did not reveal a significant change in the use of PSA-based screening as measured by the total number of PSA exams per ambulatory care visit.

Here's why Lotan said this data matters—and has implications for providers outside of UT Southwestern.

1. Why did you decide to conduct this research—and were you surprised by what you found?

"Policy regarding prostate cancer screening has important implications for men, as this is the most common cancer in men. We felt it was important to understand how the USPSTF recommendations impacted use of PSA at our large tertiary referral institution since we care for a large population of men.

"In many ways, I found the results reassuring since use of PSA did not change dramatically. I was not very surprised since I have two brothers who are internists and I am aware of how many guidelines they need to keep track of in any given year. It is difficult to change their practice with each new recommendation."

2. The actor Ben Stiller recently wrote an essay on how a PSA test "saved his life." His PSA test appears not to be in line with the current USPSTF recommendations. If his cancer had been discovered later, does the evidence suggest he still would have responded to treatment? Would you say that Stiller's claims are warranted?

"Ben Stiller's article provides important insight from a patient's perspective. He is correct that based on the USPSTF recommendation he may never have had screening.

"We know that prior to PSA screening many men were diagnosed only after they experienced metastatic disease. It is hard to know the impact of delayed diagnosis in any individual patient's case—but for a young man with intermediate-risk prostate cancer, there is no question that earlier diagnosis is preferable.

"In regards to current recommendations, the American Urological Association advocates for discussing the pros and cons of PSA screening with patients, which I think is a good policy so patients can make their own informed choices."

3. What should practicing oncologists and oncology care providers outside of UT Southwestern know about this research?

"Our institution's findings may not represent the nation as a whole; however, at least one survey dataset pointed to Texas as one of the states with the largest drop in PSA use, which we did not observe. With recent revelations about the flaws in studies used in the USPSTF recommendation, we hope the USPSTF will be diligent in considering the wisdom of their initial recommendation against PSA since this can have a significant impact on health of men.

"Future research directions are many, including looking at provider factors that may influence PSA use and finding new ways to appropriately treat men with prostate cancer and avoid treatment in men unlikely to benefit from further treatment. There is also need to optimize recommendations regarding screening for prostate cancer and developing more accurate tests."​