Origins of cancer: tackling provocative questions
ABSTRACT
Despite the tremendous progress that scientists have made throughout the history of cancer research, there are still far too many deaths and remaining scientific questions for us to be content with our current knowledge of the disease. The eighth Origins of Cancer symposium, held July 21, 2017 at Van Andel Research Institute, was organized around the theme of “Tackling Provocative Questions” to stimulate discussion of several of these unresolved paradoxes in the field of cancer research. The symposium highlighted recent progress from the National Cancer Institute’s Provocative Questions Initiative, a program that offers research support to scientists who propose innovative strategies to address one of the featured questions. Accordingly, each of our eight distinguished speakers had received funding through this Initiative or performs research that closely aligns with one of these important yet understudied questions. From microbes to biomarkers to immunotherapy, this meeting report describes the latest advancements that were presented at the symposium.
INTRODUCTION
The 2017 Origins of Cancer symposium pushed the boundaries of understudied and overlooked aspects of cancer research. The symposium boasted eight renowned clinicians and scientists whose research is funded by or closely aligns with the mission of the National Cancer Institute’s (NCI’s) Provocative Questions Initiative. Established by former National Institutes of Health (NIH) director, Dr. Harold Varmus, the Provocative Questions Initiative has sought to shed light on controversial, unanswered, and truly provocative questions in the cancer field since 2011 [1]. This year’s symposium highlighted recent findings related to five of the provocative questions: (1) “what are the underlying molecular mechanisms that are responsible for the functional differences between benign proliferative diseases and premalignant states?”; (2) “how do microbiota affect the response to cancer therapies?”; (3) “how do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?”; (4) “what cancer models or other approaches can be developed to study clinically stable disease and the subsequent transition to progressive disease?”; and (5) “can we develop bifunctional small molecules that will couple oncoproteins or other cancer-causing molecules of interest to inactivating processes such as degradation and achieve tissue-specific loss of function?”
The symposium began with an introduction and overview of the Provocative Questions Initiative by NCI’s Program Director for the Initiative, Dr. Emily Greenspan. Dr. Greenspan shared that since 2011, the Initiative has received over 2,000 grant applications resulting in over 200 new R01 and R21 awards, totaling over $200 million in research support. This success is attributed to the iterative cycle of question generation, evaluation, and revision, a process that includes both scientists and clinicians from multiple disciplines; frequent workshops are held around the world, hosting brainstorming sessions for experts in the cancer research field to debate the most important questions to be answered. Although the Initiative is still in its early years, recent evaluations of its success are promising. Dr. Greenspan shared that 30 of the 33 questions issued thus far have represented less than one percent of cancer literature, suggesting that these areas truly are understudied. In addition, over half of the questions’ research areas saw an increase in cancer literature since the inception of the program. On average, each award funded by the Initiative has produced four publications, and these publications are cited twice as frequently as those not funded by the Initiative. Clearly, the NCI’s support of innovative and creative research promises to benefit the cancer research community and ultimately, the individuals affected by these diseases. http://www.impactjournals.com/Genes&Cancer/index.php?pii=150
oncotarget impact Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
When public speak of contemporary medicine, accuracy plays one of the most crucial roles and people’s lives are directly dependent on it. Hence, any researches related to medicine are necessary to comply with the highest standards. The issue nowadays is that any results of researches can be posted online and used as a reference without being adequately checked and approved. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this problem and attempted to develop an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been established back in 2010. The major principle of this journal is related to Altmetric scores that are used as a quality measure. That helps both readers and authors to validate publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a full publications list with corresponding scores higher than 100 as well as reports mentioned previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it creates the necessary help to anyone, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was released back in 2018 by Oncotarget and written by several experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The publication has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are willing to comprehend the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hereby, the article about melanoma, was used for citations in different news articles 69 times. Besides that, it was quoted in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This research has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive useful scientific facts. Oncotarget is glad to have the chance to share with online customers this highly appreciated and high-quality information, that is trustworthy and reliable.
Mikhail (Misha) V. Blagosklonny graduated with an MD and PhD from First Pavlov State Medical University of St. Petersburg, Russia. Dr. Mikhail V. Blagosklonny has then immigrated to the United States, where he received the prestigious Fogarty Fellowship from the National Institutes of Health. During his fellowship in Leonard Neckers’ lab at the National Cancer Institute (NCI), he was a co-author of 18 publications on various biomedical themes, including targeting HSP90, p53, Bcl2, Erb2, and Raf-1. He also was the last author for a clinical phase I/II trial article.
After authoring seven papers during a brief yet productive senior research fellowship in the El-Deiry Cancer Research Lab at the University of Pennsylvania, Dr. Blagosklonny returned to NCI to work with Tito Fojo. Together, they published 26 papers. Moreover, Dr. Blagosklonny published many of experimental research papers and theoretical papers as sole author. The abovementioned sole-author articles discussed two crucial topics. The first of these discussed selectively killing cancer cells with deregulated cell cycle or drug resistance via verifying their resistance. The outcomes and underlying notion were so revolutionary that they were incorrectly cited by other scientists as “reversal of resistance,” even though the publication was titled, “Exploiting of drug resistance instead of its reversal.” One big supporter of this concept was the world-famous scientist Arthur Pardee, with whom Dr. Blagosklonny co-authored a joint publication in 2001.
The second theme throughout Dr. Blagosklonny’s sole-author articles is a research method to develop knowledge by bringing several facts together from seemingly irrelevant areas. This results in new notions with testable forecasts, which in turn can be “tested” via analyzing the literature further. Likewise, the concept was co-authored by Arthur Pardee in a 2002 article in Nature. The first success of the new research methodology was the description of the feedback regulation of p53, as confirmed by the discovery of mdm2/p53 loop; and the explanation why mutant p53 is always overexpressed, published in 1997. The most important result revealed by Dr. Blagosklonny’s research methodology is the hyperfunction (or quasi-programmed) theory of aging and the revelation of rapamycin as an exclusively well-tolerated anti-aging drug, published in 2006. As mentioned in Scientific American, Michael Hall, who discovered mTOR in 1991, gives Dr. Blagosklonny credit for “connecting dots that others can’t even see.”
In 2002, Dr. Blagosklonny became associate professor of medicine at New York Medical College. He agreed to accept responsibilities as a senior scientist at Ordway Research Institute in Albany, New York, in 2005, before receiving another position at Roswell Park Cancer Institute as professor of oncology in 2009.
Since coming to Roswell Park Comprehensive Cancer Center in 2009, Dr. Blagosklonny has studied the prevention of cancer (an age-related disease) via stopping organism aging - in other words, “preventing cancer via staying young.” His laboratory closely worked together with Andrei Gudkov’s and conducted research on the suppression of cellular senescence, namely suppression of cellular conversion from healthy quiescence to permanent senescence. This led to the discovery of additional anti-aging medicines beyond rapamycin. The cell culture studies were complemented by studies in mice, including several models like normal and aging mice, p53-deficient mice, and mice on a high-fat diet.
Dr. Blagosklonny has also published extensively on the stoppage of cellular senescence via rapamycin and other mTOR inhibitors, life extension and cancer stoppage in mice, and combinations of anti-aging medicines to be taken by humans. A rapamycin-based combination of seven clinically available medications has been named the “Koschei Formula” and is now used for the treatment of aging in patients at the Alan Green Clinic in Little Neck, New York.
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