Kidney Cancer: Biomarker Linked to Detection and Progression

MedicalResearch.com Interview with:

Dr. David Muller, PhD  Faculty of Medicine, School of Public Health Research Fellow in Epidemiology and Biostatistics Imperial College London

Dr. Muller

Dr. David C. Muller PhD
Faculty of Medicine, School of Public Health
Research Fellow in Epidemiology and Biostatistics
Imperial College, London

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

Response: Our colleagues in the U.S. have been working on KIM-1 for years, particularly in the context of chronic kidney disease. Recently they found that KIM-1 is also elevated at the time of diagnosis of kidney cancer.

We wanted to see if KIM-1 concentrations could predict the chances of a future diagnosis of kidney cancer. We found that KIM-1 was a strong predictor of being diagnosis with kidney cancer in the next 5 years. We also found that higher pre-diagnostic KIM-1 was associated with worse survival after diagnosis.  Continue reading

Coming Soon – More Lung than Breast Cancer in Women

MedicalResearch.com Interview with:
“smoking” by shira gal is licensed under CC BY 2.0Dr. Jose M. Martín-Sánchez
IP of this study
Grupo de Evaluación de Determinantes de Salud y Políticas Sanitarias
Universitat Internacional de Catalunya
Sant Cugat del Vallès
Spain


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

Response: Breast cancer has been the first cause of death from cancer among women. However, the mortality rates of breast cancer have been decreased in the last years. This downward trend can be attributed to treatment and screening programs. On the other hand, smoking has been increased among women during the last century and the main cause of lung cancer is smoking behavior. Based on this data, we hypothesized that the lung cancer mortality could outweigh the breast cancer mortality in the next years and the main purpose of this study was to project the mortality rates of lung cancer and breast cancer in women worldwide, based in previous data and using Bayesian methods, in order to identify potential strategies of public health to reduce the impact of lung cancer. Moreover, previous works described the lung and breast cancer mortality or projected one of them in a single country. For example, we have published two articles with data of Spain one of them with the description of lung cancer mortality trend in men and women and other with the projection of lung and breast cancer among women. The information of this study provides an overall point view around the word of this problem of public health.

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Not All Pancreatic Cancers are the Same: Some Have Treatable Mutations

MedicalResearch.com Interview with:

Michael J. Pishvaian, MD, PhD Phase I Program Director Assistant Professor Lombardi Comprehensive Cancer Center Washington, DC 20007

Dr. Pishvaian

Michael J. Pishvaian, MD, PhD
Phase I Program Director
Assistant Professor
Lombardi Comprehensive Cancer Center
Washington, DC 20007

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

 Response: Pancreatic cancer is a deadly disease and will soon be the second leading cause of cancer-related death.

We have made some progress in the last few years….but despite this, patients with advanced, inoperable pancreatic cancer (which represents about 80% of pancreatic cancer patients) still only live 12 months, on average. We desperately need new therapies, AND to think “outside the box” for the treatment of pancreatic cancer.

In that context, we have been learning that there are subgroups of patients with cancer whose tumors are particularly susceptible to certain therapies – either new therapies, or in some cases, approved therapies that would have not normally been used for that disease.  These specific patient subgroups with “actionable” findings have been identified through extensive genetic and molecular characterization of a patient’s tumor.

In the past there was a cynical perspective that pancreatic cancer did not harbor any “actionable” molecular abnormalities.

We have now demonstrated that:

1) There are clearly and undeniably patients with pancreatic cancer whose tumors do indeed harbor “actionable” findings.  This represents at least 27% of pancreatic cancer patients, but may represent up to 50% as new therapies evolve.  These percentages are also highly consistent with similar publications in the pancreatic cancer field over the last few years; and

2) Importantly, we have been following our patients longitudinally for outcomes, and while it is still early, there is a statistically significant improvement in progression-free survival when a patient with a specific actionable molecular abnormality is treated with the appropriately “targeted” therapy.  This finding is also consistent with findings that have been observed in other cancer types.   Continue reading

Anti-PD1 Immunotherapy May Work Better in Older Melanoma Patients

MedicalResearch.com Interview with:

Ashani Weeraratna, Ph.D. The Ira Brind professor and  Co-program leader of the Immunology, Microenvironment and Metastasis Program  The Wistar Institute Member of Wistar’s Melanoma Research Center Philadelphia 

Dr. Weeraratna

Ashani Weeraratna, Ph.D.
The Ira Brind professor and
Co-program leader of the Immunology, Microenvironment and Metastasis Program
The Wistar Institute
Member of Wistar’s Melanoma Research Center
Philadelphia 

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

Response:  This study shows for the first time that older patients, especially those who have had prior MAPKi therapy fare better than younger patients when treated with anti-PD1. We found that tumors in younger patients and younger mice have higher levels of Tregulatory cells, the cells that regulate other immune cells. This is not true systemically, only within the tumor microenvironment.

We were surprised because we expected that, as with targeted therapy, older patients would have a poorer response to immunotherapy, given what we perceive as a poorer immune system in older patients.  Continue reading

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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Circulating Cell Scoring System Identifies High Risk Prostate Cancer

MedicalResearch.com Interview with:

Dr. Yong-Jie Lu Reader in Medical Oncology Centre for Molecular Oncology Barts Cancer Institute - a CR-UK Centre of Excellence Queen Mary University of London John Vane Science Centre, Charterhouse Square, LONDON

Dr. Yong-Jie Lu

Dr. Yong-Jie Lu MBBS, MD, PhD
Reader in Medical Oncology
Centre for Molecular Oncology
Barts Cancer Institute – a CR-UK Centre of Excellence
Queen Mary University of London
John Vane Science Centre, Charterhouse Square
London

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

Response: Identifying/monitoring the occurrence of metastasis and the prediction of the length that a patient may survive with a prostate cancer is critical for doctors to select the proper treatment, aiming to achieve the best control of the cancer with a balance of quality of life. Currently this is achieved mainly by analysing the cancer tissues acquired through very invasive procedures or by expensive imaging techniques, most of which expose the patient to toxic radioactive materials.

Circulating tumour cells (CTCs), which play a key role in the metastasis process, have been shown for their potential to be used for cancer prognosis by a simple blood sample analysis. However, previous CTC studies mainly detect the epithelial type of CTCs. Using the ParsortixTM (ANGLE plc) cell-size and deformability based CTC isolation system, we analysed not only epithelial CTCs, but also CTCs with epithelial-mesenchymal transition (EMT), a cellular process associated with cancer invasion and metastasis.

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Preclinical Study Finds Cancer Stem Cell Inhibitor Sensitizes Colon Cancer Cells To Immunotherapy

MedicalResearch.com Interview with:
Dr. Yuan Gao

Assistant Investigator at Boston Biomedical

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

Response: Colorectal cancer (CRC) is the third most commonly diagnosed malignant disease and third most frequent cause of cancer-related death in the United States. Standard treatment for unresectable metastatic CRC currently includes first and second line 5-fluorouracil (5-FU)-based chemotherapy regimens. However, CRC patients often develop chemoresistance. Recently, immunotherapy has emerged as a revolutionary new treatment for CRC. However, with the exception of a small percentage of CRC patients that display microsatellite instability (MSI), the vast majority of colorectal cancer patients have been found to be resistant to immune checkpoint therapies.

Cancer stem cells (CSCs), a highly malignant tumor cell subpopulation capable of self-renewal, are considered to be fundamentally responsible for malignant growth and tumor recurrence. Emerging evidence indicates that CSCs and cancer stemness pathways, such as STAT3, beta-Catenin, CD44 and Nanog, are involved in the immune evasion of cancers. BBI-608 (napabucasin) is an orally-administered first-in-class cancer stemness inhibitor that works by targeting STAT3. In this study, we investigated the effect of cancer stemness inhibition on sensitizing colorectal cancer to immune checkpoint inhibitors in preclinical models.

In the syngeneic microsatellite stable (MSS) tumor model, CT26, an anti-PD-1 antibody delivered as a monotherapy, produced low level and temporary antitumor activity with rapid development of complete resistance to anti-PD-1 treatment. The anti-PD-1 antibody-treated CT26 tumors exhibited increased p-STAT3 activation and overexpression of a variety of stemness factors, as well as enrichment of sphere-forming stemness-high cancer cells. Napabucasin was able to reduce basal as well as anti-PD1-induced STAT3 activation and other CSC features within CT26 tumors. The combination of a stemness inhibitor – napabucasin – with the anti-PD-1 antibody led to tumor complete response (CR) in all treated CT26 tumors, with 40 percent of the mice remaining tumor-free for 30 days following treatment termination. This combination also had a synergistic effect on the influx of tumor infiltrating CD8+ T cells, which likely contributed to the rapid tumor regression. Finally, mice CR-induced by napabucasin and the anti-PD-1 antibody were able to reject CT26 tumors upon re-challenge, but not the unrelated breast cancer 4T1 tumors.

MedicalResearch.com: What should readers take away from your report?

Response: Our data suggest cancer stemness pathways contribute to immunotherapy resistance in MSS CRC, a subtype representing the vast majority of colorectal cancer cases. Furthermore, inhibition of cancer stemness by BBI-608 sensitizes colorectal cancer to immune checkpoint inhibition, producing striking regression in a large proportion of the tumors treated.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: This study provides compelling preclinical evidence to support the investigation of the combination of napabucasin with immune checkpoint inhibitors in CRC. While this study specifically investigated the combination with anti-PD-1, the combination with other immunotherapies could be studied as well.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation: AACR 2017 Abstract

Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

More Medical Research Interviews on MedicalResearch.com

Gene-silencing RNAs Targeting CTNNB1 and PD-L1 May Attack a Variety of Cancers

MedicalResearch.com Interview with:
Dr. Youzhi Li

Vice President at Boston Biomedical 

MedicalResearch.com: What are the main findings?

Response: RNAi (RNA interference) technology has the potential to target any genes causing disease, including conventionally “undruggable” targets in cancer. One particularly interesting RNAi target in oncology is the CTNNBI oncogene, which encodes the β-Catenin protein whose nuclear form acts as a transcription factor promoting tumorigenesis. Aberrant β-Catenin signaling has been demonstrated in 90 percent of colorectal carcinomas, 40 percent of hepatocellular carcinoma, and 90 percent of non-ductal pancreatic carcinomas. Recent research also suggests active β-Catenin contributes to tumor immune evasion and to the recurrence of melanoma in patients post the check-point blockage immunotherapy.

However, the direct blockade of β-Catenin activity has proved difficult with conventional approaches. While the application of traditional RNAi technology has the potential to block this pathway, in clinical cancer therapy, this approach has proven challenging due to the difficulty in systemic delivery of RNAi to tumor sites located in various organs.

We have recently developed BBI-801, a lipid-based nanoparticle that encapsulates therapeutic aiRNAs targeting CTNNB1 and PD-L1 to simultaneously target immune evasion via both these pathways. Here, we investigate the in vivo delivery and anti-tumor activity of BBI-801.

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Granzyme B Probe Plus PET Scanning Helps Determine Response To Immunotherapy

MedicalResearch.com Interview with:

Ben Larimer, PhD research fellow in lab of Umar Mahmood, MD, PhD Massachusetts General Hospital Professor, Radiology, Harvard Medical School

Dr. Ben Larimer

Ben Larimer, PhD research fellow in lab of
Umar Mahmood, MD, PhD

Massachusetts General Hospital
Professor, Radiology, Harvard Medical School

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

Response:
Although immunotherapies such as checkpoint inhibitors have revolutionized cancer treatment, unfortunately they only work in a minority of patients. This means that most people who are put on a checkpoint inhibitor will not benefit but still have the increased risk of side effects. They also lose time they could have spent on other therapies. The ability to differentiate early in the course of treatment patients who are likely to benefit from immunotherapy from those who will not greatly improves individual patient care and helps accelerate the development of new therapies.

The main purpose of our study was to find a way to separate immunotherapy responders from non-responders at the earliest time point possible, and develop an imaging probe that would allow us to distinguish this non-invasively.

Granzyme B is a protein that immune cells use to actually kill their target. They keep it locked up in special compartments until they get the right signal to kill, after which they release it along with another protein called perforin that allows it to go inside of tumor cells and kill them. We designed a probe that only binds to granzyme B after it is released from immune cells, so that we could directly measure immune cell killing. We then attached it to a radioactive atom that quickly decays, so we could use PET scanning to noninvasively image the entire body to see where immune cells were actively releasing tumor-killing granzyme B.

We took genetically identical mice and gave them identical cancer and then treated every mouse with checkpoint inhibitors, which we knew would result in roughly half of the mice responding, but we wouldn’t know which ones until their tumors began to shrink. A little over a week after giving therapy to the mice, and before any of the tumors started to shrink, we injected our imaging probe and performed PET scans. When we looked at the mice by PET imaging, they fell into two groups. One group had high PET uptake, meaning high levels of granzyme B in the tumors, the other group had low levels of PET signal in the tumors. When we then followed out the two groups, all of the mice with high granzyme B PET uptake ended up responding to the therapy and their tumors subsequently disappeared, whereas those with low uptake had their tumors continue to grow.

We were very excited about this and so we expanded our collaboration with co-authors Keith Flaherty and Genevieve Boland to get patient samples from patients who were on checkpoint inhibitor therapy to see if the same pattern held true in humans. When we looked at the human melanoma tumor samples we saw the same pattern, high secreted granzyme levels in responders and much lower levels in non-responders.

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Trunk and Branch Drivers Distinguish Early vs Late Mutations in Hepatocellular Carcinoma

MedicalResearch.com Interview with:
Sara Torrecilla Recio

PhD Student
Mount Sinai Liver Cancer Program – Division of Liver Diseases Icahn School of Medicine at Mount Sinai
New York, NY

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

Response: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which represents the second-leading cause of cancer related death worldwide. The landscape of molecular alterations in HCC has been thoroughly explored using next-generation sequencing technologies in single biopsies of tumors. However, in the recent years it has been demonstrated that not all the regions of a tumor harbor the same molecular alterations. This intra-tumor heterogeneity may lead to a misinterpretation of the molecular landscape of the malignancy since not all the molecular alterations would be captured by single-biopsies.

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Model of RAF Inhibitor Action Provides Roadmap For Resistant Colon and Thyroid Cancer Treatment

MedicalResearch.com Interview with:

Poulikos I. Poulikakos, PhD Assistant Professor Department of Oncological Sciences Department of Dermatology The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai

Dr. Poulikakos

Poulikos I. Poulikakos, PhD
Assistant Professor
Department of Oncological Sciences
Department of Dermatology
The Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai

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

Response: Mutations in the oncoprotein kinase BRAF are found in about 8% of human tumors, including more than 50% of melanomas. Small molecule RAF inhibitors prolonged survival of melanoma patients with mutant-BRAF tumors, but resistance limits their effectiveness. Further, RAF inhibitors showed only modest efficacy in patients with colorectal and thyroid mutant-BRAF tumors. Previous studies have suggested that the complex biochemical mechanisms of action of RAF inhibitors account for both sensitivity and major mechanisms of resistance to these drugs. Recently, a number of next generation RAF inhibitors have entered preclinical or clinical development, but the most appropriate clinical context for their use remained elusive.

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Effect of Centralization on Health Disparities in Lung and Bladder Cancer Surgery

MedicalResearch.com Interview with:

Emanuela Taioli MD PhD Professor, Population Health Science and Policy, and Thoracic Surgery Director, Institute for Translational Epidemiology Director, Center for the Study of Thoracic Diseases Outcome Director, Division of Social Epidemiology Icahn Medical Institute, New York, NY 10029

Dr. Taioli

Emanuela Taioli MD PhD
Professor, Population Health Science and Policy, and Thoracic Surgery
Director, Institute for Translational Epidemiology
Director, Center for the Study of Thoracic Diseases Outcome
Director, Division of Social Epidemiology
Icahn Medical Institute,
New York, NY 10029 

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

Response: Extensive literature documenting the relationship between hospital volume and clinical outcomes has resulted in the centralization of cancer care advocating patients to seek cancer surgical procedures at high-volume (HV) hospitals. Lung resection and cystectomy have been specifically recommended for centralization, but improvements in outcomes are not shared equally among racial groups. It has also been reported that black patients more commonly undergo surgery at low-volume and lower-quality hospitals, despite living in close proximity to higher quality hospitals.

We investigated the effects of centralization on HV hospital utilization and surgical outcomes for lung (n = 28,047 White; n = 2,638 Black) and bladder (n = 7,593 White; n = 567 Black) cancer patients over a 15 year time span (1997-2011) in New York State. We hypothesized that centralization has improved utilization of HV hospitals and outcomes for both black and white patients, but significant disparities remain between black and white patients.

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Diabetes Drug Reverses Aging Medium That Promotes Melanoma

MedicalResearch.com Interview with:

Reeti Behera, Ph.D. Postdoctoral fellow in the Weeraratna lab The Wistar Institute Philadelphia PA

Dr. Behera

Reeti Behera, Ph.D.
Postdoctoral fellow in the Weeraratna lab
The Wistar Institute
Philadelphia PA

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

Response: Malignant melanoma is an aggressive disease and is the cause of the majority of skin cancer deaths. In particular, older individuals have a much poorer prognosis for melanoma and are more resistant to targeted therapy than compared to young individuals. A recently published study from our lab has shown that age-related changes in secreted factors in the microenvironment can drive melanoma progression and therapy resistance.

Klotho is a protein whose expression levels decreases with aging. In this study, we have shown that a decrease in klotho levels in the aged microenvironment drives melanoma aggression and therapy resistance by promoting the oncogenic signaling pathway Wnt5A. We also have shown that reconstituting klotho levels in the aged microenvironment by using rosiglitazone, an FDA-approved drug used to treat diabetes, can reduce tumor burden in aged mice. We also show that Klotho expression is decreased in therapy-resistant melanoma tumors. Reconstituting klotho levels in therapy-resistant melanoma cells by treating with rosiglitazone can inhibit Wnt5A levels and MAPK pathway. We also show that rosiglitazone can significantly decrease therapy-resistant tumor burden in the aged mice, but not in the young.

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False Positive Mammograms Can Lead Women To Delay or Skip Next Exam

MedicalResearch.com Interview with:

Mammogram showing small lesion - Wikipedia

Mammogram showing small lesion
– Wikipedia

Firas Dabbous, PhD
Manager, Patient Centered Outcomes Research
Russell Institute for Research & Innovation
Advocate Lutheran General Hospital
Park Ridge, IL 

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

Response: When women are told that there is something abnormal on their screening mammogram that can cause stress and worry while undergoing additional testing, even when they are later told that there is nothing wrong. We wanted to know if receiving a false positive screening mammogram would cause women to think twice before getting their next screening mammogram, and maybe delay coming back for their next screen. This is important because patients who have a false positive experience may have higher chance to develop breast cancer at a later point in time. Therefore, it is important to understand their screening patterns to better educate and inform them about the importance of adhering to mammography guidelines and emphasize the importance of returning on schedule for their next screens.

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ER-beta May Identify Breast Cancer Patients For Whom Chemotherapy is Sufficient

MedicalResearch.com Interview with:
Helena Jernström, PhD
Associate Professor in Experimental Oncology
Study Coordinator for Graduate studies Division of Oncology and Pathology
Coordinator of the programmes in statistics and epidemiology for doctoral students at the Medical Faculty, Lund University
Division of Oncology and Pathology, Department of Clinical Sciences, Lund
Lund University Cancer Center/Kamprad
Lund, Sweden

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

Response: There is a need for better predictive markers to guide selection of therapy in breast cancer patients. Estrogen receptor beta (ER-beta) may confer prognostic information beyond what is currently obtained by the established clinical markers, including ER-alpha, which is routinely evaluated.

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Novel microRNA Regulatory Network Has Important Therapeutic Implications in Rhabdomyosarcoma

MedicalResearch.com Interview with:
Riccardo Taulli, PhD
Assistant Professor of Biochemistry
Dept. of Oncology, University of Turin
Via Santena 5, 10126
Torino, Italy

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

Response: Rhabdomyosarcoma is a muscle-derived pediatric cancer for which therapeutic options have not improved significantly over the past decades, especially for its metastatic form. MicroRNAs are small regulatory molecules that control gene expression at the post-transcriptional level, fine tuning a wide number of cellular mechanisms, processes and behaviors. In our work, we underwent a large microRNA isolation and sequencing effort using human samples of the three major rhabdomyosarcoma subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential.
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