Targeted Therapies for Pancreatic Cancer and Hurdles Ahead

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with a median survival of 6 months after diagnosis. Intrinsic resistance to chemotherapeutics and lack of effective targeted therapies are the major factors contributing to dismal prognosis. Several important genetic alterations (i.e., mutations, deletions) have been identified to be involved in the initiation and progression of pancreatic cancer, including KRAS and inactivation of tumor suppressors, such as TP53, SMAD4 and CDKN2A. Unique tumor microenvironment with excessive stroma due to desmoplastic reaction is one of the major characteristics of PDAC, promoting tumor growth and leading to treatment failures. In addition, tumor stroma represents an important biological barrier for drug delivery and successful treatment of PDAC. Small interfering RNA (siRNA) has recently emerged as a potential and targeted therapeutic approach which is now evaluated in clinical trials. However, siRNAbased therapeutics face important challenges, including rapid serum degradation, poor tumor cell uptake and cellular uptake, leading to off-target effects. Therefore, there is a great need for the development of safe and effective nanoparticles for better tumor-specific delivery of anti-cancer therapeutics. In this article, the main challenges in the treatment of pancreatic cancer and recent advancements on nano delivery systems of chemotherapeutics and gene-targeted agents, used both in preclinical and clinical trials are reviewed.

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy

“…Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers (∼6% at 5 years post-diagnosis) and is projected to become the second most common cause of cancer related death by 2030 (1,2). Intrinsic chemotherapyresistance is one of the major clinical problems associated with PDAC, resulting in the failure of currently available therapeutic options (3). Adjuvant chemotherapy in patients with resected PDAC has been shown to extend survival over surgery alone, and more recently, more intensive regimens such as FOLFIRONOX have been shown to be even more effective (4).…”

Unraveling ERBB network dynamics upon betacellulin signaling in pancreatic ductal adenocarcinoma in mice

“…While mortality rates are declining for many cancers due to early detection and improved treatment, rates for PDAC are still rising (Siegel et al, 2018), promoting PDAC to the top three cancer killers within the next decade (Rahib et al, 2014). Standard PDAC treatment includes surgical resection and adjuvant chemotherapy with FOLFIRINOX or gemcitabine in combination with nab-paclitaxel providing the most promising results (Aslan et al, 2018). However, systemic chemotherapy is associated with severe side effects.…”

Pharmacometabolomics Identifies 3-Hydroxyadipic Acid, d-Galactose, Lysophosphatidylcholine (P-16:0), and Tetradecenoyl-l-Carnitine as Potential Predictive Indicators of Gemcitabine Efficacy in Pancreatic Cancer Patients

“…Haas et al reported no significant difference in overall survival for KRAS wild-type vs. mutant patients, and KRAS mutation status is predictive rather than prognostic in advanced PC (34). Efforts focused on targeting PC have been disappointing (7,36), so the standard of care for PC continues to be chemotherapy. However, chemoresistance is a major challenge in the treatment of PC (14,15,17,18).…”

“…Therefore, chemotherapy plays a critical role in the therapeutic management of PC in patients with unresectable PC (4)(5)(6). Recent years have witnessed the rapid development of revolutionary targeted therapies and immune therapies, but these therapies have not shown significant results in PC (7)(8)(9). Thus, cytotoxic drugs remain the backbone of treatment for PC.…”