Cancer cells are addicted to numerous non-oncogenic traits that enable them to thrive. Proteotoxic stress is one such non-oncogenic trait that is experienced by all tumor cells owing to increased genomic abnormalities and the resulting synthesis and accumulation of non-stoichiometric amounts of cellular proteins. This imbalance in the amounts of proteins ultimately culminates in proteotoxic stress. p97, or valosin-containing protein (VCP), is an ATPase whose function is essential to restore protein homeostasis in the cells. Working in concert with the ubiquitin proteasome system, p97 promotes the retrotranslocation from cellular organelles and/or degradation of misfolded proteins. Consequently, p97 inhibition has emerged as a novel therapeutic target in cancer cells, especially those that have a highly secretory phenotype. This review summarizes our current understanding of the function of p97 in maintaining protein homeostasis and its inhibition with small molecule inhibitors as an emerging strategy to target cancer cells.

p97 is an ATPase that works in concert with histone deacetylase 6 (HDAC6), to facilitate the degradation of misfolded proteins by autophagosomes. p97 has also been implicated in DNA repair and maintaining genomic stability. In this study we determined the effect of combined inhibition of p97 and HDAC6 activities in mantle cell lymphoma (MCL) cells. We report that treatment with p97 inhibitors induces dose-dependent apoptosis in MCL cells. The p97 inhibitor CB-5083 induces ER stress markers GRP78 and CHOP and results in the accumulation of polyubiquitylated proteins. Co-treatment with CB-5083 and the HDAC6 inhibitor ACY-1215 result in marked downregulation of CDK4, Cyclin D1 and BRCA1 levels without inhibiting autophagic flux. Consequently, treatment with CB-5083 accentuates DNA damage in response to treatment with ACY-1215 resulting in enhanced accumulation of H2AX-γ and synergistic apoptosis. Furthermore, ATM loss severely impairs phosphorylation of 53BP1 following co-treatment with CB-5083 and ACY-1215 in response to gamma irradiation. Finally, co-treatment CB-5083 and ACY-1215 results in reduced tumor volumes and improves survival in Z138C and Jeko-1 xenografts in NSG mice. These observations suggest that combined inhibition of p97 and HDAC6 abrogates resolution of proteotoxic stress and impairs DNA repair mechanisms in MCL cells.

Cancer is a devastating disease condition and is the second most common etiology of death globally. After decades of research in the field of hematological malignancies and cellular therapeutics, we are still looking for therapeutic agents with the most efficacies and least toxicities. Curcumin is one of the cancer therapeutic agents that is derived from the Curcuma longa (turmeric) plant, and still in vitro and in vivo research is going on to find its beneficial effects on various cancers. Due to its potency to affect multiple targets of different cellular pathways, it is considered a promising agent to tackle various cancers alone or in combination with the existing chemotherapies. This review covers basic properties, mechanism of action, potential targets (molecules and cell-signaling pathways) of curcumin, as well as its effect on various solid and hematological malignancies.

e15744 Background: FOLFIRINOX (FFN) and Gemcitabine plus nab-paclitaxel (GN) have been established as first line chemotherapy in advanced pancreatic cancer (PC). But there is no head-to-head randomized trial data available to support preferable first line choice between these two regimens. Methods: We retrospectively evaluated 154 chemotherapy-naïve locally advanced and metastatic PC patients treated with FFN or GN at KU Cancer Center between January 2011 and November 2016. FFN consisted of Oxaliplatin 85mg/m2, Irinotecan 180mg/m2, 5-FU 400mg/m2 as a bolus and 2,400 mg/m2over 46 hour on days 1 and 15 every 4 weeks. GN consisted of Gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day1,8,15 every 4 weeks. We compared characteristics, efficacy and adverse events between FFN and GN. Results: 107 patients were treated with FFN and 47 patients with GN as first line therapy. Demographic and baseline characteristics (FFN/GN) were as follows: Median age 61/63 years, ECOG performance status (0-1): 90% / 83%, Gender (male): 57% / 54%, distant metastases: 52%/70%, biliary stenting: 41%/20%, locally advanced tumor: 48%/30%, pancreatic head tumors: 63%/55%, median number of cycles: 4/4 respectively. Objective response rate (13% vs. 10%), Stable disease rate (76% vs 82%) and disease control rate (89% vs. 92%, p = 0.5) were similar in FFN and in GN. Median PFS was 11.7 months (95% CI: 7.2-16.1) in FFN and 5.7 months (95% CI: 2.7-8.8) in GN [p = 0.07]. Median OS was 15.9 months (95% CI: 13.7-18.1) in FFN and 10.8 months (95% CI: 7.1 – 14.5) in GN [p = 0.17]. Incidences of grade 3 or higher adverse effects were neutropenia (33% vs. 17%), anemia (14% vs 31%), thrombocytopenia (28% vs 6%), elevated creatinine (2.8% vs 4%), elevated transminases (3.7% vs 6%), diarrhea (5% vs. 0%), and peripheral neuropathy (6% vs. 6%) respectively. Conclusions: Patients treated with FFN showed statistically better PFS compared to GN. However this difference in PFS did not translate into statistically significant difference in OS. Response rates were similar. Incidences of adverse events were relatively more with FFN compared to GN as expected.