Chemotherapy Choice Can Be Aided By Assessing TDP Profile

MedicalResearch.com Interview with:

Ed Liu, M.D President and CEO The Jackson Laboratory (JAX)

Dr. Ed Liu

Ed Liu, M.D
President and CEO
The Jackson Laboratory (JAX)

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: A few years ago we and others identified a complex genomic instability profile commonly found in the genomes of breast, ovarian and endometrial carcinomas, which is characterized by hundreds of isolated head-to-tail duplications of DNA segments, called tandem duplications. We refer to this configuration as the tandem duplicator phenotype, or TDP.

In this study, we perform a meta-analysis of over 2,700 cancer genomes from over 30 different tumor types and provide a detailed description of six different types of TDP, distinguished by the presence of tandem duplications of different sizes. Collectively, these profiles are found in ~50% of breast, ovarian and endometrial carcinomas as well as 10-30% of adrenocortical, esophageal, stomach and lung adeno-carcinomas. We show that distinct genetic abnormalities associate with the distinct TDPs, clearly suggesting that distinct molecular mechanisms are driving TDP formation. In particular, we provide strong evidence of a casual relationship between joint abrogation of the BRCA1 and TP53 tumor suppressor genes and the emergence of a short-span (~11 Kb) TDP profile. We also observe a significant association between hyper-activation of the CCNE1 pathway and TDP with medium-span (~230 Kb) tandem duplications, and between mutation of the CDK12 gene and medium- and large-span TDP (coexisting 230 Kb and 1.7 Kb tandem duplications).

Importantly, we find that different forms of TDP result in the perturbation of alternative sets of cancer genes, with short-span TDP profiles leading to the loss of tumor suppressor genes via double transections, and larger-span TDP profiles resulting in the duplication (i.e. copy number gain) of oncogenes and gene regulatory elements, such as super-enhancers and disease-associated SNPs.  Continue reading

Blood Pressure Med Linked to Increased Risk of Pancreatic Cancer in Postmenopausal Women

MedicalResearch.com Interview with:

Zhensheng Wang, M.P.H., Ph.D. Postdoctoral Associate Duncan Cancer Center-Bondy Baylor College of Medicine Houston, TX, US

Dr. Wang

Zhensheng Wang, M.P.H., Ph.D.
Postdoctoral Associate
Duncan Cancer Center-Bondy
Baylor College of Medicine
Houston, TX

MedicalResearch.com: What is the background for this study?

Response: Our prior research consistently found a significant inverse association between circulating levels of soluble receptor for advanced glycation end products (sRAGE), an anti-inflammatory factor, and risk of pancreatic cancer. It has also been found that sRAGE levels or RAGE signaling are modulated by anti-hypertensive (anti-HT) medications, including angiotensin-converting-enzyme inhibitors (ACEi), β-blockers, and calcium channel blockers (CCBs). These medications have been shown in prior pre-clinical or experimental research to either increase sRAGE concentrations, decrease formation of advanced glycation end-products (AGEs), or dampen pro-inflammatory receptor for AGE (RAGE) signaling pathway. We therefore hypothesized that there would be an inverse association between use of anti-HT medications and risk of developing pancreatic cancer.

Pancreatic cancer is a major public health concern in the United States, as it is the 4th leading cause of cancer-related mortality with an estimated of 43,090 deaths in 2017. Pancreatic cancer typically occurs in elderly individuals who also have chronic comorbid medical conditions, such as hypertension. Anti-HT medication use in individuals ≥ 18 years old has increased from 63.5% in 2001-2002 to 77.3% in 2009-2010, according to the National Health and Nutrition Examination Survey in the U.S. Therefore, it is of great public health significance to address the potential association between anti-HT medication use and risk of pancreatic cancer in the general population.

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Rhabdomyosarcoma Can Develop From Hijacked Blood Vessel Cells

MedicalResearch.com Interview with:

Mark E. Hatley, M.D., Ph.D. Assistant Member Molecular Oncology Division, Department of Oncology St. Jude Children's Research Hospital Memphis, TN 38105

Dr. Hatley

Mark E. Hatley, M.D., Ph.D.
Assistant Member
Molecular Oncology Division, Department of Oncology
St. Jude Children’s Research Hospital
Memphis, TN 38105

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma occurring in children. Tumors appear histologically and genetically as undifferentiated skeletal muscle and are thus thought to solely originate from early skeletal muscle cells. However, tumors occur throughout the body, including sites devoid of skeletal muscle. In addition, tumor location is a key feature of staging and 40% of patients develop RMS in the head and neck. Interestingly, head and neck muscle development is distinct from the development of trunk and limb muscle. Previously we described a model of rhabdomyosarcoma which occurred specifically in the head and neck and originated from non-muscle cells. In this study we investigated how normal development programs are hijacked to drive rhabdomyosarcoma location.

We demonstrated that RMS can originate from immature blood vessel cells that lie in between muscle fibers specifically in the head and neck. During development, these cells are hijacked, and become reprogrammed into rhabdomyosarcoma rather than mature endothelial cells. These RMS cells express factors important in head and neck muscle development. Our findings highlight that cell of origin contributes to RMS location and may explain why a high proportion of RMS occurs in the head and neck.  Continue reading

Most Baby Boomers Still Aren’t Screened For Hepatitis C

MedicalResearch.com Interview with:

In the United States, hepatitis A, hepatitis B and hepatitis C are the most common types, but also included are hepatitis D and E. CDC/ E.H. Cook, Jr.

Hepatitis Virions
CDC/ E.H. Cook, Jr.

Dr. Monica Kasting PhD first author
Dr. Anna Giuliano PhD
Susan. T. Vadaparampil, Ph.D., M.P.H.
Senior Member/Professor
Center for Infection Research in Cancer
H. Lee Moffitt Cancer Center, Tampa,
Florida.Department of Cancer Epidemiology,
H. Lee Moffitt Cancer Center,
Tampa, Florida 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: In the U.S., approximately 1 in 30 baby boomers are chronically infected with hepatitis C virus. Half of all cases of liver cancer are caused by hepatitis C and liver cancer is one of only three cancer types that are actually increasing in incidence in the US. Because of this, in 2012 the CDC issued a recommendation for universal screening for hepatitis C virus for everyone born between 1945 and 1965 (baby boomers). We wanted to look at the time period after that to see if the rates of screening in that population increased. From 2013-2015 screening among baby boomers only increased by 0.9% (from 11.8% to 12.7%) which indicates we still have a long way to go before we meet our goal of universal screening.  Continue reading

Gut and Pancreatic Microbiome Drive Pancreatic Cancer

MedicalResearch.com Interview with:

Mautin Hundeyin MD Post-doctoral Research Fellow

Dr. Hundeyin

Mautin Hundeyin MD
Post-doctoral Research Fellow

George Miller, MD is Principal Investigator and Director of the S. Arthur Localio Laboratory in the Department of Surgery at NYU School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Pancreatic ductal adenocarcinoma (PDA) is the devastating disease with grim prognosis. The microbiome has emerged as a contributor to oncogenesis in a number of intestinal tract malignancies. We found that PDA is associated with a distinct stage-specific gut and pancreatic microbiome that drives disease progression by inducing intra-tumoral immune suppression. Targeting the microbiome protects against oncogenesis, reverses intra-tumoral immune-tolerance, and enables efficacy for check-point based immunotherapy. These data have implications for understanding immune-suppression in pancreatic cancer and its reversal in the clinic.  Continue reading

Wistar Study Targets Telomeres To Treat Resistant Melanoma

MedicalResearch.com Interview with:
Gao Zhang, Ph.D.
Staff scientist in the Herlyn Lab
The Wistar Institute

MedicalResearch.com: What is the background for this study?

Response: The past 7 years have witnessed the great success in treating patients with unresectable or metastatic melanoma. Despite the breakthrough of molecularly targeted therapies and immune checkpoint blockade therapies, a majority of patients have experienced the rapid tumor recurrence and progression, following the dramatic regression. There is an urgent and unmet need to treat therapy-resistant tumors.

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Animal Study Finds Tiny Dose of Sildenafil (Viagra) May Reduce Colon Cancer Risk

MedicalResearch.com Interview with:

Darren D. Browning, PhD | Professor Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University Georgia Cancer Center, Augusta, Georgia 30912-2100

Dr. Darren Browning

Darren D. Browning, PhD | Professor
Department of Biochemistry and Molecular Biology,
Medical College of Georgia at Augusta University
Georgia Cancer Center,
Augusta, Georgia 30912-2100

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Cancer of the colon and rectum is one of the most commonly diagnosed and has a high mortality because it is often identified at an advanced stage. In the United States the average overall risk of having to deal with this disease at some point is around one in twenty-five, but the risk is much higher for people who have previously had polyps removed or if a close relative was diagnosed with colon cancer. The risk is even higher for patients with inflammatory bowel disease or heritable disorders such as familial adenomatous polyposis and lynch syndrome. While chemoprevention is clearly warranted, there are currently no drugs available that can reduce the risk for those predisposed to colorectal cancer.

Previous work from our laboratory has shown that drugs like sildenafil that inhibit phosphodiesterase 5 (PDE5), have a profound effect on the epithelial lining of the intestine. Our recent work has shown that these drugs can prevent intestinal cancers in two different mouse models of human disease. While this class of drugs is best known for treating erectile dysfunction, due to a low side-effect profile they are also prescribed for long-term daily use to treat pulmonary arterial hypertension (PAH) and benign prostate hyperplasia

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Patients With Dementia Less Likely To Receive Chemotherapy for Colon Cancer

MedicalResearch.com Interview with:

Yingjia Chen, M.Sc, MPH, Ph.D. Postdoctoral Fellow University of California, San Francisco

Dr. Chen

Yingjia Chen, M.Sc, MPH, Ph.D.
Postdoctoral Fellow
University of California, San Francisco 

MedicalResearch.com: What is the background for this study?

Response: Both colon cancer and dementia are prevalent among the elderly and have a high risk of co-occurrence. Previous studies found that patients with dementia were treated less aggressively. In this study, we hypothesized that presence of pre-existing dementia was associated with worse survival for stage III colon cancer patients, and that post-operative chemotherapy was on the causal pathway.

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Periodontal Disease is Associated with Higher Risk of Cancer in Postmenopausal Women

MedicalResearch.com Interview with:

Jean Wactawski-Wende, PhD Dean, SUNY Distinguished Professor Professor, Department of Epidemiology and Environmental Health School of Public Health and Health Professions University of Buffalo

Dr. Wactawski-Wende

Jean Wactawski-Wende, PhD
Dean, SUNY Distinguished Professor
Professor, Department of Epidemiology and Environmental Health
School of Public Health and Health Professions
University of Buffalo

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There has been a growing interest in the role of periodontal disease in system chronic diseases, including cancer. We explored the association of periodontal disease history and incident cancer in the women’s health initiative study of postmenopausal women. We found that women reporting periodontal disease history were at increased risk of developing cancer overall. In addition they were found to have significant increased risk of specific cancers including cancers of the lung, breast, esophagus, gallbladder and melanoma. The risk persisted after control for many other factors. In addition, the risk was seen in women regardless of their smoking history. Both ever smokers and never smokers were found to have increased risk of cancer associated with periodontal disease history.

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Phase III Study of Stivarga (Regorafenib) For Progressed Hepatocellular Carcinoma

MedicalResearch.com Interview with:

Dr. Jordi Bruix, MD Professor of Medicine University of Barcelona Director of the Barcelona Clinic Liver Cancer (BCLC) Group Liver Unit Hospital Clinic of Barcelona

Dr. Bruix

Dr. Jordi Bruix, MD
Professor of Medicine
University of Barcelona
Director of the Barcelona Clinic Liver Cancer (BCLC) Group Liver Unit
Hospital Clinic of Barcelona

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The RESORCE Phase III pivotal trial is an international, multicenter, placebo-controlled trial which investigated the efficacy of Stivarga (regorafenib) in adults with Child-Pugh A and Barcelona Clinic Liver Cancer Stage Category B or C hepatocellular carcinoma (HCC) who had documented disease progression following first-line treatment with Nexavar (sorafenib).

Trial participants were administered a daily oral 160mg dose (three weeks on/ one week off) of regorafenib plus best supportive care (BSC), or placebo plus BSC.

Results from the trial demonstrated that participants treated with regorafenib experienced a statistically significant and clinically meaningful improvement in the study’s primary endpoint—overall survival (OS). Participants treated with regorafenib demonstrated a median overall survival of 10.6 months vs. 7.8 months with placebo.

At ASCO 2017, an exploratory analysis evaluated the impact of baseline alpha-fetoprotein (AFP) and c-Met as predictors of poor prognosis in patients enrolled in the RESORCE trial (Abstract #4078).

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