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President Barack Obama’s “Cancer Moonshot” now has a scientific flight plan. It calls for better cooperation among researchers and institutions, aggressive pursuit of immunotherapy and making better use of proven cancer prevention strategies. Called the Blue Ribbon Panel Report, the document was approved September 7 by the National Cancer Advisory Board, part of the National Cancer Institute. Five months in the making, the report’s 10 recommendations for research priorities were put together by a 28-member group of cancer experts appointed last April. It’s the most specific direction yet for the moonshot (SN: 4/2/16, p. 20), launched when Obama announced the intention to make the United States “the country that cures cancer once and for all” in his State of the Union address in January. Vice President Joe Biden, whose son Beau died in 2015 from brain cancer at age 46, has been leading the charge. If the vice president formally adopts the recommendations, they could form the foundation for research grants awarded through the National Institutes of Health. But that depends largely on the U.S. Congress providing funding for the moonshot, which has not yet happened. The report doesn’t contain dramatic surprises and doesn’t veer far off course from current cancer research. That’s largely by design. The goal of the panel was to come up with a plan to make “10 years of progress in five years” by hastening those areas with the most promise, which also stand to affect large numbers of patients. “We want it to be a pushy evolution, not a revolution,” says Stan Gerson, director of the Case Comprehensive Cancer Center in Cleveland, who was not on the panel. “There are some things here that are right on the money where we ought to be focused.” The Cancer Moonshot’s Blue Ribbon Panel presented 10 research recommendations to the National Cancer Advisory Board on September 7. Patients would enter genetic information about their cancer into a national database, making it easier to find and participate in clinical trials. A clinical trials network devoted exclusively to immunotherapies would focus on what’s considered one of the most promising advances in cancer treatment. More research is needed to understand drug resistance, a major cause of death from cancer. This system would link many of the nation’s largest data repositories, enabling free, one-stop access for researchers, doctors and patients to share data. Intensify research on the major drivers of childhood cancers More research into the biology of pediatric and adolescent cancers could lead to improved treatments. Guidelines are needed to minimize and manage the often excruciating side effects of treatment. Expand use of proven prevention and early detection strategies Researchers need to identify ways to increase adherence to proven strategies, such as the HPV vaccine, especially in medically underserved populations and those with inherited genetic risks. Researchers should analyze stored tumor tissue from patients who received standard treatment to search for genetic and other factors that predict which people would benefit from standard care versus experimental treatment. Aweb-based catalog that maps the genetic and cellular evolution of tumors would enable researchers to develop predictive models of tumor progression and response to treatment. More public–private sector collaborations are needed to develop new technologies to help doctors deliver more effective therapies to patients. If there is any underlying thread to the report, it is that progress depends on greater cooperation in research and improvements in patient engagement. “There’s not a lot new under the sun in terms of the areas they have targeted. The most important concept here with the vice president’s efforts is that he can serve as an accelerant at a time when we’re at an inflection point in treating cancer,” says Gary Gilliland, president and director of the Fred Hutchinson Cancer Research Center in Seattle. “Within 10 years if we don’t get to a place where we’ve got curative approaches to essentially all cancers then we’ve failed — and shame on us.” For treatment, the report singles out immunotherapy, which harnesses a patient’s own immune system to fight cancer. The strategy is widely regarded as one of the most significant advances in cancer care, even though so far only 10 to 20 percent of patients receiving such treatments show long-term benefit. “When I speak to my patients, I tell them that the greatest risk is disappointment,” says medical oncologist David Gerber of the University of Texas Southwestern Medical Center in Dallas. Nonetheless, he and others remain optimistic about immunotherapy’s potential, and he agrees with recommendations to speed up research. In proposing an immunotherapy clinical trials network, the report states that current treatments “represent only the tip of the iceberg of what is possible.” Since the moonshot began, Biden has crisscrossed the country, touring cancer research centers, holding photo ops and meeting with doctors. In June, he presided over a cancer summit at Howard University in Washington, D.C. One theme Biden has stressed at these events — and was reflected in the panel’s report — is the need for better data sharing. Traditionally, raw scientific data remains the property of the institutions and researchers who conduct studies. But this can impede collaboration — between institutions or across disciplines — and make it harder to find patterns within genetics and biology that might reveal how cancer appears and grows. The new report acknowledges the problem with research silos, stating that “our ability to accelerate progress against cancer demands that researchers, clinicians and patients across the country collaborate in sharing their collective data and knowledge about the disease.” Among the recommendations is the creation of a National Cancer Data Ecosystem, a one-stop, free collection of data that will allow patients to upload and receive data about their specific type of tumor. While Obama heralded the moonshot as a cure for cancer, Gerson, from the Case Comprehensive Cancer Center, would also like to see more scientists take on less flashy issues, finding better ways to save lives in known ways. Among them: “How do we get people to stop smoking?” he says. “We’re not doing it well.” Tyler Jacks, the report cochair and director of the Koch Institute for Integrative Cancer Research at MIT, said during a news conference that the panel recognizes that progress against cancer is about “emphasizing the use of known prevention strategies. It’s not just about treatment.” In discussing prevention, the report notes low rates of adoption for the human papillomavirus vaccine, which protects against the virus that causes cervical and other cancers, and for colorectal cancer, or CRC, screening. “If we understood better the reasons these proven cancer prevention strategies are not being widely used and how we could increase uptake of these strategies,” the report states, “we could reduce deaths due to cervical cancer by 90 percent, CRC by up to 70 percent and lung cancer by as much as 95 percent.” The authors also note that many people carry inherited genetic risks for cancer and don’t know it, and improved screening for genetic predisposition could save lives. What happens to the moonshot after this year depends largely on Congress. The report will eventually be forwarded to the vice president and the moonshot task force he oversees. The panel did not say how much the recommendations would cost. But in his budget request for fiscal year 2017, Obama asked for $680 million for additional funding to pay for the moonshot. The panel members confined themselves to scientific matters but noted that barriers to cancer progress are not just about research. Disparities keep many patients from getting treatments today, much less improvements coming tomorrow. “The one concern I have is that they put off the side policy issues as being out of scope for the Blue Ribbon Panel. I think it’s appropriate, but in the end it’s the policy issues that are going to determine the success of the entire program,” says Gilliland. “How do you get coverage and reimbursement? How do you ensure privacy if you’re sequencing everybody’s genome? How do you address access to clinical trials? Those are some of the very hardest problems, and if we don’t solve them it’s not going to matter how clever we are in the laboratory or how sensitive our techniques are for early detection.”

Kanwal R.,Case Western Reserve University | Gupta S.,Case Western Reserve University | Gupta S.,Case Comprehensive Cancer Center
Journal of Applied Physiology | Year: 2010

Epigenetic modifications are central to many human diseases, including cancer. Traditionally, cancer has been viewed as a genetic disease, and it is now becoming apparent that the onset of cancer is preceded by epigenetic abnormalities. Investigators in the rapidly expanding field of epigenetics have documented extensive genomic reprogramming in cancer cells, including methylation of DNA, chemical modification of the histone proteins, and RNA-dependent regulation. Recognizing that carcinogenesis involves both genetic and epigenetic alterations has led to a better understanding of the molecular pathways that govern the development of cancer and to improvements in diagnosing and predicting the outcome of various types of cancer. Studies of the mechanism(s) of epigenetic regulation and its reversibility have resulted in the identification of novel targets that may be useful in developing new strategies for the prevention and treatment of cancer. © 2010 the American Physiological Society.

Kanwal R.,Case Western Reserve University | Gupta S.,Case Western Reserve University | Gupta S.,University Hospitals Case Medical Center | Gupta S.,Case Comprehensive Cancer Center
Clinical Genetics | Year: 2012

Cancer initiation and progression is controlled by both genetic and epigenetic events. The complexity of carcinogenesis cannot be accounted for by genetic alterations alone but also involves epigenetic changes. Epigenetics refers to the study of mechanisms that alter gene expression without altering the primary DNA sequence. Epigenetic mechanisms are heritable and reversible, and include changes in DNA methylation, histone modifications and small noncoding microRNAs (miRNA). Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Aberrant epigenetic modifications probably occur at a very early stage in neoplastic development, and they are widely described as essential players in cancer progression. Recent advances in epigenetics offer a better understanding of the underlying mechanism(s) of carcinogenesis and provide insight into the discovery of putative cancer biomarkers for early detection, disease monitoring, prognosis, and risk assessment. In this review, we summarize the current literature on epigenetic changes causing genetic alterations that are thought to contribute to cancer, and discuss the potential impact of epigenetics future research. © 2011 John Wiley & Sons A/S.

Thakur V.S.,Case Western Reserve University | Gupta K.,Case Western Reserve University | Gupta S.,Case Western Reserve University | Gupta S.,Case Comprehensive Cancer Center
Carcinogenesis | Year: 2012

Green tea polyphenols (GTPs) reactivate epigenetically silenced genes in cancer cells and trigger cell cycle arrest and apoptosis; however, the mechanisms whereby these effects occur are not well understood. We investigated the molecular mechanisms underlying the antiproliferative effects of GTP, which may be similar to those of histone deacetylase (HDAC) inhibitors. Exposure of human prostate cancer LNCaP cells (harboring wild-type p53) and PC-3 cells (lacking p53) with 10-80 μg/ml of GTP for 24 h resulted in dose-dependent inhibition of class I HDAC enzyme activity and its protein expression. GTP treatment causes an accumulation of acetylated histone H3 in total cellular chromatin, resulting in increased accessibility to bind with the promoter sequences of p21/waf1 and Bax, consistent with the effects elicited by an HDAC inhibitor, trichostatin A. GTP treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels in these cells. Furthermore, treatment of cells with proteasome inhibitor, MG132 together with GTP prevented degradation of class I HDACs, compared with cells treated with GTP alone, indicating increased proteasomal degradation of class I HDACs by GTP. These alterations were consistent with G 0-G 1 phase cell cycle arrest and induction of apoptosis in both cell lines. Our findings provide new insight into the mechanisms of GTP action in human prostate cancer cells irrespective of their p53 status and suggest a novel approach to prevention and/or therapy of prostate cancer achieved via HDAC inhibition. © The Author 2011. Published by Oxford University Press. All rights reserved.

Megahed A.I.,University Hospitals Case Medical Center | Koon H.B.,Case Comprehensive Cancer Center
Current Treatment Options in Oncology | Year: 2014

The approval of ipilimumab and inhibitors of the BRAF pathway for the treatment of melanoma has provided multiple therapeutic options for patients. Although these new agents improve survival compared with chemotherapy alone, the majority of patients will progress and will receive chemotherapy at some point in the course of their disease. Whether the clinical efficacy of chemotherapy can be improved by targeting resistance mechanisms is an area of active investigation. In addition, chemotherapy may be of use modulating the efficacy of the newer agents. © 2014 Springer Science+Business Media.

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