State of the art biological therapies in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival rate of approximately 5%. Several target agents have been tested in PDAC, but almost all have failed to demonstrate efficacy in late phase clinical trials, despite the better understanding of PDAC molecular biology generated by large cancer sequencing initiatives in the past decade. Eroltinib (a small-molecule tyrosine-kinase inhibitor of epidermal growth factor receptor) plus gemcitabine is the only schedule with a biological agent approved for advanced pancreatic cancer, but it has resulted in a very modest survival benefit in unselected patients. In our work, we report a summary of the main clinical trials (closed and ongoing) that refer to biological therapy evaluation in pancreatic cancer treatment.

Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

“…The microenvironment of PDACs is characterized by a highly desmoplastic stroma encompassing up to 90% of the tumor [3,4], heterogeneous vascularization [6], regions with hypoxic tissue [7], and interstitial hypertension [8]. Treatment strategies targeting the desmoplastic tumor stroma have not been beneficial to PDAC patients thus far [4,9].…”

“…The majority of the patients receive gemcitabin or FOLFIRINOX chemotherapy alone or in combination with radiation therapy [2,3], resulting in a five year survival of only $6% [1]. Several approaches of targeted treatment have been explored, however, with limited therapeutic effect [4,5].…”

“…The microenvironment of PDACs is characterized by a highly desmoplastic stroma encompassing up to 90% of the tumor [3,4], heterogeneous vascularization [6], regions with hypoxic tissue [7], and interstitial hypertension [8]. Treatment strategies targeting the desmoplastic tumor stroma have not been beneficial to PDAC patients thus far [4,9]. Low microvascular density (MVD) and reduced blood flow have been shown to be signs of tumor aggressiveness [10][11][12], and high MVD in peripheral hot spots has been found to correlate with poor prognosis, suggesting that highly heterogeneous microcirculation aggravates the outcome [6,13].…”

Opportunities and Resistance to Signal-Targeted Therapies in Pancreatic Cancer: What Can we Learn from Proteomic Studies?

“…In PDAC, the efficacy of about 15 targeted therapies was evaluated in combination mostly with chemotherapy, Gemcitabine [18] and shown in details in Table 3. Despite an initial anti-tumor response of patients to these targeted therapies as described by an ameliorated general state of the patients, resistance is induced very quickly.…”

Opportunities and Resistance to Signal-targeted Therapies in Pancreatic Cancer: What Can We Learn from Proteomic Studies?

“…These may be intracellular inhibitors (small chemical molecules such as protein or lipid kinase inhibitors) or extracellular inhibitors (biological drugs such as monoclonal antibodies to receptor tyrosine kinase RTK or their ligands) ( Table 1). Targeted In PDAC, the efficacy of about 15 targeted therapies was evaluated in combination mostly with chemotherapy, Gemcitabine [18] and shown in details in Table 3. Despite an initial anti-tumor response of patients to these targeted therapies as described by an ameliorated general state of the patients, resistance is induced very quickly.…”