Drug development has been highly challenging and replete with failure stories of pipeline agents investigated in pancreatic cancer, despite treatment algorithms being dramatically improved in many oncology indications. The very low success rate in clinical development stems to a great extent from pancreatic tumours being highly resistant to treatment. This is attributed to thick stromal tissue within pancreatic tumours which in turn contributes to immuno-suppression and limited access of therapies to the tumour site.
Volkan Gunduz, PhD, Oncology and Hematology Senior Analyst at GlobalData, said: “While previous clinical development programs directly targeted tumour cells, current clinical development includes Phase III programmes which are specifically or co-targeting stromal tissue along with the tumour itself.”
Among these agents is AbbVie and Johnson & Johnson’s Bruton’s tyrosine kinase (BTK) inhibitor Imbruvica (ibrutinib), which eliminates tumour promoting survival signals from the tumour microenvironment. Another therapeutic candidate, Halozyme’s PEGPH20 (pegvorhyaluronidase alfa) degrades hyaluronan, a component of the tumour stroma and thereby makes the tumour tissue more permeable to drug delivery.
Meanwhile, preclinical research is identifying novel targets that could inspire further clinical development. Recently, emerging research from University of Texas MD Anderson Cancer Center in Houston identified Dickkopf-3 (DKK3) protein to be highly abundant in pancreatic tumour stroma. Targeting DKK3 in mouse models of pancreatic cancer resulted in immune cell infiltration and prolonged survival. Compared to healthy individuals, DKK3 levels are four and a half times higher in people with pancreatic cancer, making it a feasible therapeutic candidate.
Gunduz added: "While pancreatic cancer progresses rapidly following diagnosis, it is estimated that it takes an average of about ten years from the initiating tumorigenic mutation to formation of a sizeable tumour and metastatic spread to other parts of the body.
"There is a large window of opportunity here, where a better understanding of the disease evolution in this time frame could lead to development of more specific early diagnostic techniques, more effective novel treatment approaches, and identification of patient populations that will benefit most from novel therapies.”
