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.

MedicalResearch.com: What are the main findings?

Response: We applied a combination of pathway- and network-based approaches to abnormal transcriptome profiles of pancreatic ductal adenocarcinoma. Our results suggested that DRD2 up-regulation, most likely due to a posttranscriptional aberration, may contribute to malignancy. Also, tissue microarray analysis (TMA) of DRD2 across normal pancreatic tissues and PDAC sections revealed that DRD2 protein levels were significantly increased in PDAC compared to normal samples. This led to the identification of DRD2, which we validated as a novel promising therapeutic target. Our findings confirmed the efficacy of DRD2 blockade to suppress cancer cell proliferation, survival and migration potential in vitro.

Using in vivo model of pancreatic cancer, RNAi knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the haloperidol, a FDA approved drug for DRD2 inhibition, to mice with orthotopic xenograft tumors reduced final tumor size and metastasis.

We found that DRD2 blockade has an anti-proliferative effect in pancreatic cancers, while activating ER stress, in line with previous studies reporting that the deficiency of DRD2 induces ER stress. Excessive ER stress leads to cell cycle arrest and apoptosis, and has emerged as an attractive anti-cancer therapeutic avenue. As such, inhibiting DRD2 provides a targeted approach to activate ER stress in cancer cells.

Importantly, when compared to normal samples, DRD2 expression was elevated significantly in CP, which is a known major risk factor for PDAC, suggesting that DRD2 overexpression may be involved in early steps of PDAC development.

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

Response: Our study highlights the potential of DRD2 antagonism as a possible therapeutic approach for pancreatic cancer, which could be facilitated through a drug-repositioning strategy. This also motivates future studies to investigate possible relationships between DRD2 levels and different PDAC subtypes, emerged by transciptome and metabolite profiling, which may lead to a better understanding of DRD2 function in PDAC, and help with tailoring therapy for individual patients.

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

Response: Our findings from this study identified DRD2 inhibitors as potential therapy against pancreatic cancer. DRD2 inhibitors are already used against neurological disorders. Therefore, given the positive results from our study, this will allow drug repositioning facilitating the transition of DRD2 inhibitors for pancreatic cancer treatment to the clinic.

Citation:

Gastroenterology. 2016 Aug 28. pii: S0016-5085(16)34982-4. doi: 10.1053/j.gastro.2016.08.040. [Epub ahead of print]
Expression of DRD2 is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice.
Jandaghi P1, Najafabadi HS2, Bauer AS3, Papadakis AI4, Fassan M5, Hall A6, Monast A7, von Knebel Doeberitz M8, Neoptolemos JP9, Costello E9, Greenhalf W9, Scarpa A10, Sipos B11, Auld D2, Lathrop M2, Park M12, Büchler MW13, Strobel O13, Hackert T13, Giese NA13, Zogopoulos G6,Sangwan V14, Huang S4, Riazalhosseini Y15, Hoheisel JD3.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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