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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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

Lutathera® Approved for Neuroendocrine Tumors of the Pancreas (Steve Job’s Cancer)

MedicalResearch.com Interview with:

Dr- Lynn Matrisian

Dr. Matrisian

Lynn Matrisian, PhD, MBA
Chief science Officer
Pancreatic Cancer Action Network

MedicalResearch.com: Would you tell us a little about PNETs? How common is this type of pancreatic tumor? How does Lutathera differ from other treatments for this tumor? 

Response: Pancreatic neuroendocrine tumors (PNETs) make up about 6 percent of all pancreatic cancer diagnoses. They are less common and slower growing than the more common type of pancreatic cancer, adenocarcinoma, and have a better prognosis.

Lutathera® is a peptide receptor radionuclide therapy (PRRT) that was approved for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including PNETs, that express somatostatin receptors. The drug is a somatostatin analog that is conjugated to a radionuclide (177Lu) to selectively deliver radiotherapy to the cancer cells.

Other treatment options for PNETs include surgery (partial or complete removal of the tumor), chemotherapy (typically in combination) or radiation therapy (conventional as well as PRRT). Patients may also receive targeted therapies. Sutent® blocks platelet-derived growth factor receptors (PDGFRs) α and β, stem-cell factor receptor (c-kit) and vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3, leading to inhibition of cell growth and angiogenesis. Afinitor® behaves as a rapamycin analog, blocking the mammalian target of rapamycin (mTOR) signaling pathway.

Prior to Lutathera’s approval, there were two non-PRRT somatostatin analogs approved for PNET patients. These drugs were initially intended to mitigate some of the symptoms of the disease, but they were also found to slow the cancer cells’ growth. The approved somatostatin analogs are lanreotide and octreotide.  Continue reading

DNA Analysis Identifies Subtype of Pancreatic Cancer With Good Prognosis

MedicalResearch.com Interview with:

Nancy You, MD, MHSc, FACS Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston

Dr. You

Nancy You, MD, MHSc, FACS
Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center
Houston 

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

Response: This study was motivated by the emerging promise of precision medicine and the emerging evidence that immunotherapy may have phenomenal efficacy in particular molecular subtypes of cancers.  This specific molecular subtype shows deficiency in DNA mismatch repair mechanisms and therefore is thought to be more immunogenic.  DNA mismatch repair deficiency can arise from germline defects such as in the case of patients with Lynch Syndrome, an inherited cancer syndrome, or from epigenetic inactivation DNA mismatch repair genes.

Overall, pancreas cancer has seen limited success with conventional chemotherapy.  In our study, we demonstrated that there is a particular molecular subtype of pancreas cancer that is characterized by defect in DNA mismatch repair genes and by microsatelie instability that has a different prognosis than other pancreas cancers.  This subtype of pancreas cancer is suspected to also respond to immunotherapy.

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Comprehensive Study of Metabolic Inhibitors Reveals the Anti-Tumor Efficacy of Phenformin in Pancreatic Cancer

MedicalResearch.com Interview with:

Dr-Rajesh-Kumar.jpg

Dr. Rajesh Kumar NV

Rajesh Kumar NV, Ph.D.
Instructor of Oncology and Pathology,
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Current affiliation
Senior Manager, Human Therapeutics Division,
Intrexon Corporation
Germantown, MD

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

Response: Pancreatic ductal adenocarcinoma (a.k.a. pancreatic cancer) is one of the most deadly of all types of cancer and currently the third leading cause of cancer-related death in United States. Current therapeutic options for pancreatic cancer involve combination cytotoxic chemotherapy, which yield only minimal survival benefit. A multitude of Phase III clinical trials have failed to demonstrate efficacy, largely due to the aggressive growth of pancreatic tumors. Metabolic reprogramming is a hallmark of cancer cells, including pancreatic cancer. Altered metabolism is central to the pathogenesis of pancreatic cancer and contributes to promotion of proliferation, survival, invasiveness and chemo-resistance of cancer cells. Pharmacologic strategies targeting cancer metabolism might therefore represent a promising approach towards the development of effective drugs against pancreatic cancer.

We utilized a clinically relevant and genetically characterized platform of patient-derived pancreatic cancer xenografts, which we originally created from the freshly resected pancreatic cancer tissues of patients, to explore the in vivo anti-tumor efficacy of a panel metabolic inhibitors and investigated whether mutational status, gene expression and metabolite profile of tumors correlate with the sensitivity to metabolic inhibitors. To our knowledge, this is the largest preclinical trial which enrolled a large number of animals (over 500 mice) with established human pancreatic tumors for the comprehensive evaluation of key metabolic inhibitors in pancreatic cancer.  Continue reading

Distinct Mutational Signatures Correlate With Increased Immune Activity in Pancreatic Cancer

MedicalResearch.com Interview with
Dr. Ashton A. Connor, MD
PanCuRx Translational Research Initiative,
Ontario Institute for Cancer Research
Dr. Steven Gallinger MD, MSC
Division of General Surgery
Toronto General Hospital
Toronto, ON

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

Response: The etiology of pancreatic ductal adenocarcinoma (i.e. “pancreatic cancer”) and the relationship between the tumour and its characteristic dense, encroaching stroma are still poorly understood.

Using whole genome sequencing in two large cohorts, we show that there are four fundamental mutational processes that give rise to pancreatic cancer.
With expression data, we also show that the interaction between the tumour and the surrounding stroma varies with the type of mutational process found in the tumour. Specifically, tumours with defective DNA repair, either homologous recombination or mismatch repair deficiency, elicited strong anti-tumour immune responses, likely due to the relatively high numbers of neoantigens in these tumours.

Individually, these concepts have been studied in other cancer types, but we are first to apply either of these to pancreatic cancer, and we also the first to integrate these two aspects of cancer biology for any tumour, to our knowledge.

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DRD2 Inhibitors As Potential Therapy Against Pancreatic Cancer

MedicalResearch.com Interview with:
Dr. Pouria Jandaghi
Functional Genome Analysis, Deutsches Krebsforschungszentrum
Heidelberg, Germany
Department of Human Genetics, McGill University
University and Genome Quebec Innovation Centre
Montreal, Canada

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

Response: Although the overall five-year survival of all patients with cancer stands at 63%, for pancreatic cancer patients, it is a disheartening 8% – a number that remains largely unchanged for three decades. Of the patients diagnosed with pancreatic cancer, about 85% exhibit pancreatic ductal adenocarcinoma (PDAC). Most of these patients die within 4 to 6 months after diagnosis. The poor prognosis is caused by the its detection at only late stages, and lack of effective options for chemotherapy. The widely used chemotherapeutic agent gemcitabine, confers a median survival advantage of only 6 months, and resistance to therapy develops in the vast majority of patients. Given this poor prognosis of patients with PDAC, there is an urgent need to find more effective therapies.

In this study, we set out to investigate potential therapeutic targets by dissecting gene expression profiles of tumors and control samples. Candidate targets were validated with respect to their suitability and analyzed functionally.
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New Onset Diabetes, Especially In Lean Patients, Can Be Marker of Pancreatic Cancer

MedicalResearch.com Interview with:
Dr. Pavel Škrha
Charles University, Prague
Czech Republic

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

Response: Incidence of pancreatic cancer (PAC) is still increasing. The main problem is in the late diagnosis of the cancer. It was found, that diabetes mellitus was much more frequent in the pancreatic cancer patients than in the general population. DM can be already the first symptom of the disease (secondry T3cDM).

In our study nearly 80 % of all the pancreatic cancer patients had DM/prediabetes and it was of new-onset (less than 2 years before the cancer diagnosis) in 73 % out of them. We have measured the current marker of PAC (CA 19-9) together with serum microRNA-196 and -200 (that we have chosen in the previous pilot study). All the markers were significantly elevated in the pancreatic cancer patients, without any difference between the subgroups according to DM presence/absence. While the sensitivity of CA 19-9 alone (to detect the cancer) was 85 % (specificity 73 %), combining all the three markers improved it to 95 % (specificity 77 %). In the pancreatic cancer group, there were only six patients with T1 or T2 stage (others had an advanced stage of the disease – T3, T4). While CA 19-9 alone identified only 2 patients of them, the combined test identified all the six patients (data not shown in the poster). Continue reading

Vitamin A May Inhibit Pancreatic Cancer by Preventing Desmoplasia That Surrounds Tumor

MedicalResearch.com Interview with:

Armando E. del Río Hernández, PhD European Research Council Fellow Head, Cellular and Molecular Biomechanics Laboratory http://biomechanicalregulation-lab.org/ Senior Lecturer, Department of Bioengineering Imperial College London

Dr. del Río Hernández

Armando E. del Río Hernández, PhD
European Research Council Fellow
Head, Cellular and Molecular Biomechanics Laboratory
http://biomechanicalregulation-lab.org/
Senior Lecturer, Department of Bioengineering
Imperial College London

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

Response: Pancreatic cancer is an extremely aggressive disease with an unacceptably low survival rate that has not changed during the last 40 years despite significant efforts aimed at developing therapies against cancer cells.

Pancreatic cancer is characterised by an extensive desmoplasia, which forms the majority of the tissue around the tumour. This desmoplastic tissue is known to help the tumour to grow and metastasize, and hinders drug delivery.

We have focused our efforts on understanding how pancreatic stellate cells (PSCs), which are the key effectors that orchestrate the desmoplastic reaction in pancreatic cancer, can promote tumour progression. PSCs in healthy pancreas have abundant vitamin A storage in their cytoplasm and exist in a quiescent state that guarantees a balanced tissue homeostasis. In pancreatic cancer, loss of this balance activates PSCs, which lose the vitamin A content and remodel the surrounding tissue to make it favourable for cancer cell invasion.
We found that treating PSCs which ATRA (All trans-retinoic acid), the active metabolite of vitamin A mechanically reprograms PSCs to promote quiescence in vitro. Quiescent PSCs are unable to remodel the microenvironment to allow pancreatic cancer cell invasion.

To get more information about our findings please find the article in the open access journal Nature Communications:http://www.nature.com/articles/ncomms12630

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Pancreatic Cancer Study Finds Abraxane Superior to Paclitaxel

MedicalResearch.com Interview with:

Rajesh Kumar NV, Ph.D. Instructor of Oncology and Pathology Johns Hopkins University School of Medicine Baltimore, MD, USA Current Affiliation: Senior Manager, Human Therapeutics Division, Intrexon Corporation, 20358 Seneca Meadows Parkway, Germantown, MD, USA

Dr. Rajesh Kumar NV

Rajesh Kumar NV, Ph.D.
Instructor of Oncology and Pathology
Johns Hopkins University School of Medicine
Baltimore, MD, USA
Current Affiliation: Senior Manager, Human Therapeutics Division, Intrexon Corporation, 20358 Seneca Meadows Parkway, Germantown, MD, USA

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

Response: Pancreatic cancer remains as one of the most deadly malignancies in the world. Recently, a cremophor-free and albumin-bound formulation of paclitaxel (nab-PTX, Abraxane) in combination with gemcitabine (GEM, Gemzar) is recently approved as a standard of care treatment option for patients with metastatic pancreatic cancer. Majority of the newly diagnosed pancreatic cancer patients use the nab-PTX plus GEM regimen. Currently there are over 100 clinical trials at various stages with this regimen as a backbone to approved medicines or investigational agents. Since widely available cremophor-based paclitaxel (PTX, Taxol) is a key chemotherapy component for the treatment of several human malignancies and the treatment cost of nab-PTX is relatively higher than PTX, patients, clinicians, third party payers and regulatory agencies have a substantial interest in understanding whether these two drugs provide a similar level of therapeutic efficacy in pancreatic cancer.

We utilized orthotopic models of human pancreatic cancer, which were shown to better recapitulate the histologic and metastatic characteristics of disease, and compared the anticancer efficacy, effect on tumor stroma modulation, metastatic spreading to distant organs and survival following GEM, PTX, nab-PTX and combinations of GEM plus PTX or nab-PTX. The preclinical trial used a total of 300 mice with established orthotopic pancreatic tumors. The tumors used for implantation were originally resected from the primary tumors of patients with moderately differentiated and poorly differentiated pancreatic cancer.

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