Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%–90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of “precision therapeutics”. No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease.

Pancreatic cancer: treatment approaches and trends

“…Nowadays, gemcitabine is used in combination with taxol, a paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) that is commercially known as abraxane. Taxol is a microtubule dynamics inhibitor that promotes the stabilization of microtubules by preventing the catastrophe process, which induces cell cycle arrest at the G2/M phase resulting in cell death [14] . In preclinical studies, nab-paclitaxel improved the intratumoral concentration of gemcitabine.…”

“…Both environmental and inherited factors [11] can contribute to the development of this disease and the most common risk factors associated to this type of cancer are smoking [12,13] and overweight obesity [14] .…”

“…When compared to other resected solid tumors, the poorest outcomes are observed in patients with resected pancreatic cancer. After surgery, those resected patients are selected for adjuvant therapy with chemoradiation or chemotherapy alone and they present a median survival post-surgery combined with adjuvant therapy averaging 2 years [14] , with only 20% of patients reaching 5-year survival rate [18] . Regarding that, there are some studies with neoadjuvant chemotherapy administered in patients with resectable, borderline resectable or locally advanced disease aiming to increase resectability by achieving higher margin-negative resections and conversion rates [19] .…”

Predictive biomarkers for chemotherapies in pancreatic cancer

“…Pancreatic cancer is the fourth leading cause of cancer-related mortality (1) in developed countries and it is expected to become the second one (2). Increased mortality in this pathology is mainly related to the advanced stages at diagnosis, cases in which practically the moment for curative resection has been already exceeded (3).…”

The significance of Trk receptors in pancreatic cancer

“…6,7 These results underscore the need to find targeted therapies to increase response rates while minimizing toxicity, and this has been under intense investigation. [8][9][10][11][12] A number of biological agents modulating different targets are currently in clinical development including targeting epidermal growth factor receptor and other core pathways deregulated in PDAC such as PI3K/mammalian target of rapamycin (mTOR), inhibiting angiogenesis, cell cycle, matrix metalloproteinases, DNA repair, cytokines, cyclooxygenase-2, proteasome, and immune checkpoint inhibitors, as well as other strategies targeting the stroma and vaccine-based therapeutics. 9,10 However, despite this spate of investigations, very few phase-III trials have been conducted, and only one agent, erlotinib, has been approved for use by the Federal Drug Administration (FDA) in PDAC in combination with Gem in unresectable or metastatic cancer.…”