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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New Survival Prediction Model for Locally Advanced Pancreatic Cancer

MedicalResearch.com Interview with:

Dr-Dewi-VernereyDewi Vernerey PhD
Epidemiologist / Statistician
Methodology and quality of Life in oncology unit
University Hospital of Besançon

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

Response: The management of locally advanced pancreatic cancer (LAPC) patients is still controversial. Better discrimination for the prediction of overall survival (OS) at diagnosis is needed. Currently, there is a lack of a staging system and an absence of a consensus regarding patient-specific risk profile for OS that can lead to confusion about the development of research strategy and to potentially inappropriate management of patients with locally advanced pancreatic cancer.

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Study Identifies Pathway Linking Obesity With Pancreatic Cancer Progression

Rakesh K. Jain, Ph.D. A.W.Cook Professor of Radiation Oncology (Tumor Biology) Director, E.L. Steele Laboratory Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital Boston, MA 02114

Dr. Rakesh Jain

MedicalResearch.com Interview with;
Dr. Rakesh K. Jain, PhD
A.W.Cook Professor of Radiation Oncology (Tumor Biology)
Director, E.L. Steele Laboratory
Department of Radiation Oncology
Harvard Medical School and
Massachusetts General Hospital
Boston, MA 02114

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

Response: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide, and more than half of patients diagnosed with PDAC are overweight or obese. Among patients with PDAC, obesity more than doubles the already high risk of death, and our work aims to reveal the underlying mechanisms. Specifically, we identified that obesity increases desmoplasia – an accumulation of connective tissue and inflammation – hallmark of Pancreatic ductal adenocarcinoma and discovered underlying mechanisms.

In our report published online in Cancer Discovery, we describe how interactions among fat cells, immune cells and connective tissue cells in obese individuals create a microenvironment that promotes tumor progression while diminishing the response to chemotherapy. We demonstrated the negative impact of obesity on numerous aspects of tumor growth, progression and treatment response in several animal models of pancreatic ductal adenocarcinoma and confirmed some of our findings in samples from cancer patients. Along with finding that tumors from obese mice or patients exhibited elevated levels of adipocytes or fat cells and of desmoplasia, both of which fuel tumor progression and interfere with treatment response, we identified the underlying causes.

The elevated desmoplasia in obese mouse models of PDAC was caused by the activation of pancreatic stellate cells through the angiotensin II type-1 receptor (AT1) signaling pathway. This activation was induced by interleukin-1 beta (IL-1ß) produced by fat cells as well as the immune cells called neutrophils within tumors. Inhibiting AT1 signaling with losartan, which is used clinically to treat hypertension, or the blockade of IL-1ß reduced obesity-associated desmoplasia and tumor growth and increased the response to chemotherapy in the obese mouse model but not in normal weight animals. Analysis of tumors from human PDAC patients revealed increased desmoplasia and fat deposits in samples from obese patients, and data from more than 300 patients showed that excess weight was associated with a reduction in patients.

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Paradoxical Cell Death Mechanism Accelerates Pancreatic Cancer Growth

MedicalResearch.com Interview with:

Dr. George Miller, MD Vice Chair for research, Department of Surgery Associate Professor, Department of Surgery Associate Professor, Department of Cell Biology NYU Langone’s Perlmutter Cancer Center

Dr. George Miller

Dr. George Miller, MD
Vice Chair for research, Department of Surgery
Associate Professor, Department of Surgery
Associate Professor, Department of Cell Biology
NYU Langone’s Perlmutter Cancer Center

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

Dr. Miller: Cancer cell death is the goal of most therapeutic programs. Indeed, chemotherapy induces cancer cell death. We show that a novel form of cancer cell death entailing organized necrosis is a prominent way by which cancer cells die. However, paradoxically this form of cell death termed “necroptosis” actually accelerates pancreatic cancer growth in animals by inducing immune suppressive inflammation.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Miller: Novel agents are needed to block necroptosis in pancreatic cancer. This can potentially enhance the immune system’s ability to fight the cancer.

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