Dealing with pancreatic cancer heterogeneity

Pancreatic PDAC tumours are heterogeneous and have been recently classified into two to four distinct genetic subtypes [1,2]. In addition each individual tumour is not uniform. It contains many subclones that are more or less aggressive and is thought to include slowly proliferating cancer stem cells capable of regenerating the entire heterogenous tumour from a single cell [3].

Unfortunately in clinical trials, pancreatic cancer is often treated as if it were a single homogenous disease. For example it can be predicted that parvovirus H-1 will only be effective against pancreatic cancer with functional SMAD4 (see here). Clinical trials are often conducted in late stage pancreatic cancer that have SMAD4 deactivations. Therefore a more tailored approach should be adopted that looks for efficacy only in SMAD4 active patients. This is a common theme in drug development for pancreatic cancer. For example farnesyltransferase inhibitors are considered a failed drug for pancreatic cancer however there are reports of complete response in some patients which presumably has a molecular mechanism at its core [4]. If the mechanism could be discovered through basic R&D, a screen to predict which patients would respond to farnesyltransferase inhibitors could be developed. It would then be worthwhile reapplying for FDA approval.

Importantly it has been found in breast cancer cells that when tumour heterogeneity is taken into account in preclinical models then stable disease can be achieved using standard chemotherapeutics [5]. The idea is based on maintaining a stalemate between aggressive and nonaggressive breast cancer cells by applying a lower than normal dose of therapeutic that does not select for highly aggressive metastatic clones. Pancreatic cancer is crying out for such a study. It is heterogenous and at present chemotherapy is the only viable treatment.

Refs

  1. Waddell, Nicola, Marina Pajic, Ann-Marie Patch, David K. Chang, Karin S. Kassahn, Peter Bailey, Amber L. Johns, et al. ‘Whole Genomes Redefine the Mutational Landscape of Pancreatic Cancer’. Nature 518, no. 7540 (25 February 2015): 495–501. doi:10.1038/nature14169.
  2. Moffitt, Richard A., Raoud Marayati, Elizabeth L. Flate, Keith E. Volmar, S. Gabriela Herrera Loeza, Katherine A. Hoadley, Naim U. Rashid, et al. ‘Virtual Microdissection Identifies Distinct Tumor- and Stroma-Specific Subtypes of Pancreatic Ductal Adenocarcinoma’. Nature Genetics 47, no. 10 (October 2015): 1168–78. doi:10.1038/ng.3398.
  3. Hiley, Crispin, Elza C. de Bruin, Nicholas McGranahan, and Charles Swanton. ‘Deciphering Intratumor Heterogeneity and Temporal Acquisition of Driver Events to Refine Precision Medicine’. Genome Biol 15, no. 8 (2014): 453. http://www.biomedcentral.com/content/pdf/s13059-014-0453-8.pdf.
  4. Orchard­-Webb D​. 2015. ​Future Directions in Pancreatic Cancer Therapy​. JOP. Journal of the Pancreas 16​:249­-255.
  5. Enriquez-Navas, Pedro M., Yoonseok Kam, Tuhin Das, Sabrina Hassan, Ariosto Silva, Parastou Foroutan, Epifanio Ruiz, et al. ‘Exploiting Evolutionary Principles to Prolong Tumor Control in Preclinical Models of Breast Cancer’. Science Translational Medicine 8, no. 327 (24 February 2016): 327ra24. doi:10.1126/scitranslmed.aad7842.
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