Strategy For Treatment Of Pancreatic Cancer Research Articles

Emerging Ablative and Transarterial Therapies for Pancreatic Cancer

AbstractPancreatic adenocarcinoma is a highly aggressive malignancy with a poor prognosis secondary to late presentation with metastases, challenging resection, and limited alternative therapies. Standard treatment strategies for pancreatic cancer include surgery, chemotherapy, and radiation therapy. These options can extend survival and/or relieve symptoms but are seldom curative. Thermal ablative therapies have been utilized in pancreatic cancer mostly in an open surgical setting. Irreversible electroporation (IRE) is a nonthermal ablative option for pancreatic cancer that uses high voltage, low energy direct current to induce cell death. IRE technology has been shown to spare critical structures such as blood vessels and bile ducts. The safety and efficacy of the percutaneous IRE in Stage 3 pancreas cancer has been studied and there is currently a Food and Drug Administration approved, randomized, controlled trial, and registry enrolling patients in the United States. Recent animal studies have also demonstrated that the advantages of IRE may extend beyond the local tumor effect. In addition to this local ablative option, a phase 3 trial is studying a transarterial option in the management of pancreatic cancer.

TRIM37 Mediates Chemoresistance and Maintenance of Stemness in Pancreatic Cancer Cells via Ubiquitination of PTEN and Activation of the AKT-GSK-3β-β-Catenin Signaling Pathway.

PurposeThe tripartite motif-containing family member TRIM37 is involved in a number of important biological and pathological processes, and it has recently been shown to be an essential regulator of protein ubiquitination and a contributor to tumorigenesis. We previously showed that TRIM37 is overexpressed in and promotes the proliferation and invasion of pancreatic cancer (PC).MethodsSphere formation, flow cytometric, qRT-PCR, western blot, colony formation, EdU incorporation, mouse xenograft model, TUNEL and IHC assays were performed to detect the role of TRIM37 in stemness and chemoresistance of PC in vitro and in vivo. Bioinformatics analysis and dual-luciferase reporter assays were used to determine which intracellular pathways might mediate the effects of TRIM37 in PC cells. Immunofluorescent(IF) staining, co-immunoprecipitation(CO-IP), protein stability and ubiquitination assays were performed to investigate the relationship between TRIM37 and PTEN.ResultsTRIM37 modulates the ubiquitination and degradation of the tumor suppressor phosphatase and tensin homolog (PTEN), which negatively regulates the AKT–GSK-3β–β-catenin signaling pathway, thereby sustaining aberrant activation of PC cells. High expression of TRIM37 combined with low expression of PTEN correlates with poor survival of PC patients.ConclusionsCollectively, our results suggest that inhibition of the TRIM37–AKT–GSK-3β–β-catenin axis may be a promising strategy for treatment of PC.

The Role of Imaging in Current Treatment Strategies for Pancreatic Adenocarcinoma.

In pancreatic cancer, imaging plays an essential role in surveillance, diagnosis, resectability evaluation, and treatment response evaluation. Pancreatic cancer surveillance in high-risk individuals has been attempted using endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI). Imaging diagnosis and resectability evaluation are the most important factors influencing treatment decisions, where computed tomography (CT) is the preferred modality. EUS, MRI, and positron emission tomography play a complementary role to CT. Treatment response evaluation is of increasing clinical importance, especially in patients undergoing neoadjuvant therapy. This review aimed to comprehensively review the role of imaging in relation to the current treatment strategy for pancreatic cancer, including surveillance, diagnosis, evaluation of resectability and treatment response, and prediction of prognosis.

A Novel E2F1-EP300-VMP1 Pathway Mediates Gemcitabine-Induced Autophagy in Pancreatic Cancer Cells Carrying Oncogenic KRAS

Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents, which participates in cell response to disease. We previously characterized VMP1 (Vacuole Membrane Protein 1) as an essential autophagy related protein that mediates autophagy in pancreatic diseases. We also demonstrated that VMP1-mediated autophagy is induced by HIF-1A (hypoxia inducible factor 1 subunit alpha) in colon-cancer tumor cell lines, conferring resistance to photodynamic treatment. Here we identify a new molecular pathway, mediated by VMP1, by which gemcitabine is able to trigger autophagy in human pancreatic tumor cell lines. We demonstrated that gemcitabine requires the VMP1 expression to induce autophagy in the highly resistant pancreatic cancer cells PANC-1 and MIAPaCa-2 that carry activated KRAS. E2F1 is a transcription factor that is regulated by the retinoblastoma pathway. We found that E2F1 is an effector of gemcitabine-induced autophagy and regulates the expression and promoter activity of VMP1. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to the VMP1 promoter in PANC-1 cells. We have also identified the histone acetyltransferase EP300 as a modulator of VMP1 promoter activity. Our data showed that the E2F1-EP300 activator/co-activator complex is part of the regulatory pathway controlling the expression and promoter activity of VMP1 triggered by gemcitabine in PANC-1 cells. Finally, we found that neither VMP1 nor E2F1 are induced by gemcitabine treatment in BxPC-3 cells, which do not carry oncogenic KRAS and are sensitive to chemotherapy. In conclusion, we have identified the E2F1-EP300-VMP1 pathway that mediates gemcitabine-induced autophagy in pancreatic cancer cells. These results strongly support that VMP1-mediated autophagy may integrate the complex network of events involved in pancreatic ductal adenocarcinoma chemo-resistance. Our experimental findings point at E2F1 and VMP1 as novel potential therapeutic targets in precise treatment strategies for pancreatic cancer.

Optimal timing and treatment strategy for pancreatic cancer.

For pancreatic adenocarcinoma (PDAC), no studies have established any association between earlier treatment initiation and long-term outcomes. In addition, an optimal type of initial treatment for the localized disease remains ill-defined. Patients in the National Cancer Database (2004-2015) with clinical stage I (CS-I) and II (CS-II) PDAC who underwent curative-intent resection were included. Optimal time from diagnosis-to-treatment including neoadjuvant chemotherapy, neoadjuvant chemoradiation, or upfront surgery was assessed. An optimal type of treatment was evaluated. The primary outcome was overall survival (OS). Among 29 167 patients, starting any treatment within 0 to 6 weeks was associated with improved median OS compared with 7 to 12 weeks (21.0 vs 20.1 months; P = .004). This persisted when accounting for sex, race, and Charlson-Deyo score (hazard ratio [HR], 0.94; P = 0.02) and on subset analysis for CS-I (23.5 vs 21.8 months; P = .04) and CS-II (19.4 vs 18.3 months; P = .03). Neoadjuvant chemotherapy was associated with improved OS compared with neoadjuvant chemoradiation (25.6 vs 22.7 months; P < .0001) or US (25.6 vs 20.1 months; P < .0001) even when accounting for sex, race, and Charlson-Deyo score (neoadjuvant chemoradiation: HR, 0.86; P < .001; US: HR, 0.79; P < .001). This improvement persisted in subset analysis with NC compared with neoadjuvant chemoradiation (CS-I: 28.6 vs 25.0 months; CS-II: 25.0 vs 22.9 months; both P < .0001) and to US (CS-I: 28.6 vs 22.9 months; CS-II: 24.7 vs 18.4 months; both P < .0001). On multivariable analysis for each CS-I/CS-II, NC remained associated with 20% improved survival compared with neoadjuvant chemoradiation or upfront surgery. For PDAC, initiation of therapy within 6 weeks from diagnosis is associated with improved survival, with neoadjuvant chemotherapy associated with the best survival compared with neoadjuvant chemoradiation or upfront surgery.

Open and Minimal Approaches to Pancreatic Adenocarcinoma.

Surgical options and approaches to pancreatic cancer are changing in the current era. Neoadjuvant treatment strategies for pancreatic cancer combined with the increased use of minimal access surgical techniques mean that the modern pancreatic surgeon requires mastering a number of surgical approaches with to optimally manage patients. Whilst traditional open surgery remains the most frequent approach for surgery, the specific steps during surgery may need to be modified in light of the aforementioned neoadjuvant treatments. Robotic and laparoscopic approaches to pancreatic resection are feasible, but these surgical methods remain in their infancy. In this review article, we summarise the current surgical approaches to pancreatic cancer and how these are adapted to the minimal access setting with discussion of the patient outcome data.

Abstract PR8: Irreversible electroporation is an effective tumor-ablation strategy that induces immunologic cell death and promotes systemic antitumor immunity

Abstract New therapeutic strategies are direly needed to treat pancreatic cancer. Over the last decade, tumor-ablation strategies, such as radiofrequency ablation, have emerged as promising therapeutic options. However, these strategies are associated with significant complications and treatment limitations. To circumvent these limitations, members of our research team developed a nonthermal tissue ablation modality, termed irreversible electroporation (IRE), for treating solid tumors. IRE delivers a series of low-energy, unipolar electric pulses through electrodes inserted directly into the tumor to produce structural defects in the target cell membrane and cell death. While the effectiveness of IRE in inducing targeted tumor ablation is well established, there is a paucity of data pertaining to immune system activation following IRE. Here, we hypothesize that IRE treatment will elicit robust proinflammatory cell death signaling and a strong anticancer immune response, ultimately leading to decreased disease burden. To evaluate this hypothesis, we utilized healthy pancreatic tissue, patient-derived xenograft (PDX) models, in vivo studies using immunocompetent mouse models, and studies in human patients. In healthy ex vivo pancreatic tissue, IRE induces predominately apoptotic cell death with limited proinflammatory effects. However, in ex vivo PDX tumors and in vivo murine pancreatic tumors, IRE induced voltage-dependent inflammatory cell death signaling, marked by the release of defined damage-associated molecular patterns (DAMPs). Mice treated with IRE exhibited 40% or more ablation of pancreatic tumors, significantly increased progression-free survival, and lower overall disease burden. IRE treatment also reduced local and systemic immunosuppressive cell populations, such as tumor-associated macrophages and T-regulatory cells, and increased proinflammatory signaling weeks after treatment. The increased proinflammatory signaling was, in part, associated with the generation of specific DAMPs and robust activation of the innate immune system. Additionally, we observed increased evidence of improved antigen presentation, altered immune checkpoint signaling pathways, and engagement of the adaptive immune system. Together, our data support a model whereby the unique cell death and tumor ablation following IRE treatment stimulate the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a proinflammatory state. Likewise, the nonthermal nature of the ablation improves tumor antigen availability. Together, these mechanisms result in robust engagement of the adaptive immune system and improved systemic antitumor immune responses. We anticipate that IRE will be highly capable of improving conventional pancreatic cancer treatment strategies and complement emerging immunomodulatory approaches targeting primary tumors, metastatic lesions, and preventing recurrence. This abstract is also being presented as Poster A11. Citation Format: Rebecca M. Brock, Natalie Beitel-White, Melvin F. Lorenzo, Veronica M. Ringel-Scaia, Sheryl Coutermarsh-Ott, Navid Manuchehrabadi, Rafael V. Davalos, Irving C. Allen. Irreversible electroporation is an effective tumor-ablation strategy that induces immunologic cell death and promotes systemic antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR8.

Evaluation of neoadjuvant therapy for pancreatic cancer: is it the best choice?

Currently the treatment strategy of pancreatic cancer has shifted from the mode surgery first to multidisciplinary team. More and more evidences have revealed that neoadjuvant therapy will help to increase the R0 resection rate, reduce the recurrence rate, and improve the prognosis of the patients with borderline resectable pancreatic cancer. Furthermore, neoadjuvant therapy is also recommended for resectable pancreatic cancer patients with high risk factors of tumor recurrence. In this article, the current controversy and research progress of neoadjuvant therapy for pancreatic cancer are reviewed and commented in order to deepen the understanding of the hot topic in clinial surgeons. Key words: Pancreatic neoplasms; Resectablity; Neoadjuvant therapy; Multidisciplinary team; Efficacy

Conversion Surgery for Pancreatic Cancer-The Impact of Neoadjuvant Treatment.

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis, mainly because only 15–20% of all patients present with resectable tumor stages at the time of diagnosis. Due to locally extended tumor growth or distant metastases upfront resection is not reasonable in the majority of patients. Considerably, PDAC will be the 2nd most frequent cause of cancer-related deaths within the next 10 years for both men and women. While there is currently no convincing evidence for the use of neoadjuvant therapy in resectable PDAC, there are controversial results from studies investigating neoadjuvant treatment concepts in borderline resectable PDAC (BR-PDAC). However, the definition of BR-PDAC is a topic of debate. While BR-PDAC has originally been defined on merely anatomical criteria, the International Association of Pancreatology (IAP) has recently suggested a broader definition based on a combination of anatomical (A) findings, biological (B) criteria (which reflect tumor aggressiveness), and conditional (C) aspects (which respect host-related condition). In case of BR-PDAC with venous invasion alone, upfront resection is generally recommended whenever technically possible in patients fit for surgery and without evidence for lymph node metastases. In contrast, in case of arterial invasion neoadjuvant therapy is regarded as the treatment of choice. The same accounts for high CA 19-9 levels, suspected or proven lymph node involvement and poor performance status. In locally advanced PDAC (LA-PDAC), neoadjuvant treatment represents the standard of care resulting in proportionally high rates of secondary resection. This “conversion” surgery offers the chance for improved survival times in an otherwise palliative situation. Herein, we summarize the current evidence of different treatment strategies for pancreatic cancer with a focus on conversion surgery and the impact of neoadjuvant treatment in this setting.

Molecular chaperone HspB2 inhibited pancreatic cancer cell proliferation via activating p53 downstream gene RPRM, BAI1, and TSAP6.

Heat shock proteins (HSPs) were known as the molecular chaperones, which play a pivotal role in the protein quality control system, ensuring correct folding of proteins, and facilitating the correct refolding of damaged proteins via the transient interaction with their substrate proteins. They also practice in the regulation of cell cycles and are involved in apoptosis. We found that HspB2 was almost completely silent in pancreatic cancer and few studies investigated the role of HspB2 in cancer cells, particularly in pancreatic cancer. Here, we reported that HspB2 effectively inhibited cell proliferation in Panc-1 cells. Specifically, we demonstrated that HspB2 could combine mut-p53 and change the DNA binding site of mutant p53, subsequently upregulated the expression of RPRM, BAI-1, and TSAP6 which were the downstream genes of wt-p53, participate in mediating downstream responses to p53, including inhibiting cell proliferation and angiogenesis. The main aim of this study is to investigate the relationship between HspB2 and p53, and provide a novel treatment strategy for pancreatic cancer.

The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

SummaryBackgroundWorldwide, both the incidence and death rates of pancreatic cancer are increasing. Evaluation of pancreatic cancer burden and its global, regional, and national patterns is crucial to policy making and better resource allocation for controlling pancreatic cancer risk factors, developing early detection methods, and providing faster and more effective treatments.MethodsVital registration, vital registration sample, and cancer registry data were used to generate mortality, incidence, and disability-adjusted life-years (DALYs) estimates. We used the comparative risk assessment framework to estimate the proportion of deaths attributable to risk factors for pancreatic cancer: smoking, high fasting plasma glucose, and high body-mass index. All of the estimates were reported as counts and age-standardised rates per 100 000 person-years. 95% uncertainty intervals (UIs) were reported for all estimates.FindingsIn 2017, there were 448 000 (95% UI 439 000–456 000) incident cases of pancreatic cancer globally, of which 232 000 (210 000–221 000; 51·9%) were in males. The age-standardised incidence rate was 5·0 (4·9–5·1) per 100 000 person-years in 1990 and increased to 5·7 (5·6–5·8) per 100 000 person-years in 2017. There was a 2·3 times increase in number of deaths for both sexes from 196 000 (193 000–200 000) in 1990 to 441 000 (433 000–449 000) in 2017. There was a 2·1 times increase in DALYs due to pancreatic cancer, increasing from 4·4 million (4·3–4·5) in 1990 to 9·1 million (8·9–9·3) in 2017. The age-standardised death rate of pancreatic cancer was highest in the high-income super-region across all years from 1990 to 2017. In 2017, the highest age-standardised death rates were observed in Greenland (17·4 [15·8–19·0] per 100 000 person-years) and Uruguay (12·1 [10·9–13·5] per 100 000 person-years). These countries also had the highest age-standardised death rates in 1990. Bangladesh (1·9 [1·5–2·3] per 100 000 person-years) had the lowest rate in 2017, and São Tomé and Príncipe (1·3 [1·1–1·5] per 100 000 person-years) had the lowest rate in 1990. The numbers of incident cases and deaths peaked at the ages of 65–69 years for males and at 75–79 years for females. Age-standardised pancreatic cancer deaths worldwide were primarily attributable to smoking (21·1% [18·8–23·7]), high fasting plasma glucose (8·9% [2·1–19·4]), and high body-mass index (6·2% [2·5–11·4]) in 2017.InterpretationGlobally, the number of deaths, incident cases, and DALYs caused by pancreatic cancer has more than doubled from 1990 to 2017. The increase in incidence of pancreatic cancer is likely to continue as the population ages. Prevention strategies should focus on modifiable risk factors. Development of screening programmes for early detection and more effective treatment strategies for pancreatic cancer are needed.FundingBill & Melinda Gates Foundation.

Gastrin vaccine improves response to immune checkpoint antibody in murine pancreatic cancer by altering the tumor microenvironment.

Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250μg) or PAS (100 and 250μg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.

Effect of Adenomatous Polyposis Coli Loss on Tumorigenic Potential in Pancreatic Ductal Adenocarcinoma.

Loss of the Adenomatous Polyposis Coli (APC) tumor suppressor in colorectal cancer elicits rapid signaling through the Wnt/β-catenin signaling pathway. In contrast to this well-established role of APC, recent studies from our laboratory demonstrated that APC functions through Wnt-independent pathways to mediate in vitro and in vivo models of breast tumorigenesis. Pancreatic ductal adenocarcinoma (PDAC) has an overall median survival of less than one year with a 5-year survival rate of 7.2%. APC is lost in a subset of pancreatic cancers, but the impact on Wnt signaling or tumor development is unclear. Given the lack of effective treatment strategies for pancreatic cancer, it is important to understand the functional implications of APC loss in pancreatic cancer cell lines. Therefore, the goal of this project is to study how APC loss affects Wnt pathway activation and in vitro tumor phenotypes. Using lentiviral shRNA, we successfully knocked down APC expression in six pancreatic cancer cell lines (AsPC-1, BxPC3, L3.6pl, HPAF-II, Hs 766T, MIA PaCa-2). No changes were observed in localization of β-catenin or reporter assays to assess β-catenin/TCF interaction. Despite this lack of Wnt/β-catenin pathway activation, the majority of APC knockdown cell lines exhibit an increase in cell proliferation. Cell migration assays showed that the BxPC-3 and L3.6pl cells were impacted by APC knockdown, showing faster wound healing in scratch wound assays. Interestingly, APC knockdown had no effect on gemcitabine treatment, which is the standard care for pancreatic cancer. It is important to understand the functional implications of APC loss in pancreatic cancer cells lines, which could be used as a target for therapeutics.

Synergy between arsenic trioxide and JQ1 on autophagy in pancreatic cancer.

Pancreatic cancer is a deadliest type of malignancy and lacks effective intervention. We here report a potential strategy for treatment of this malignancy by the combination of arsenic trioxide (ATO) and BET bromodomain inhibitor JQ1. These two agents synergistically modulate multistages of autophagy and thus induce apoptosis effectively in pancreatic cancer cells. Our genomic and biochemical data have demonstrated that crosstalks between ER stress and autophagy play crucial roles during ATO-induced apoptosis, in which NRF2 may stand at the crossroad between cell death and survival. This has been further strengthened by our finding that NRF2 depletion renders insensitive cells into sensitive ones in regard to ATO treatment-caused cell death. The knockdown of NRF2 and the addition of JQ1 result in similar molecular/cellular effects in promoting effective ATO-induced apoptosis in cells that are insensitive to ATO treatment alone. Thus, the combination of ATO and JQ1 may represent a new treatment strategy for pancreatic cancer.

Inhibition of ATM Increases Interferon Signaling and Sensitizes Pancreatic Cancer to Immune Checkpoint Blockade Therapy.

Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Because ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1- and SRC-dependent, manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1-blocking antibody in association with increased tumoral CD8+ T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer. SIGNIFICANCE: This study demonstrates that ATM inhibition induces a T1IFN-mediated innate immune response in pancreatic cancer that is further enhanced by radiation and leads to increased sensitivity to anti-PD-L1 therapy.See related commentary by Gutiontov and Weichselbaum, p. 3815.

New advances in comprehensive treatment for pancreatic cancer

Pancreatic cancer is a highly digestive system malignancy with an extremely poor prognosis. Although the rapid improvements of surgical technique have resulted in the increase in the resection rate and the significant decline in peri-operative morbidity and mortality, the prognosis of pancreatic cancer remains far from satisfying. As the understanding of tumor biological behavior deepens, the treatment strategy of pancreatic cancer has been changed from surgery first to multidisciplinary team (MDT) based comprehensive management including surgery, chemotherapy, radiotherapy and others. In the past decade, MDT modality has been employed widely in high volume pancreatic center and has improved the management of pancreatic cancer. Here, the authors reviewed the recent advances in systematic treatment for pancreatic cancer, with an aim to provide new horizons of optimal management. Key words: Pancreatic neoplasms; Pancreatic cancer; Multidisciplinary team; Comprehensive treatment; Chemotherapy; Neoadjuvant therapy

Abstract 2183: Protective autophagy elicited by RAF®MEK®ERK inhibition suggests a treatment strategy for pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma was responsible for ~43,000 deaths in the USA in 2017 and is the epitome of a recalcitrant cancer driven by an, as yet, pharmacologically intractable oncoprotein, KRAS. Although the clinical picture remains grim, the mechanisms by which key alterations in tumor suppressors and proto-oncogenes contribute to PDA have been dissected. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis. However, to date, pharmacological inhibition of this pathway has provided no clinical benefit to PDA patients. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling in PDA cell lines elicits autophagy, a process of cellular recycling that protects pancreatic cancer cells from the potentially cytotoxic effects of KRAS pathway inhibition. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro, and promotes regression of xenografted patient-derived PDA tumors in mice. Finally, treatment of a PDA patient with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers such as PDA. Citation Format: Conan G. Kinsey, Soledad A. Camolotto, Amelie M. Boespflug, Katrin P. Guillen, Mona Foth, Amanda Truong, Sophia S. Schuman, Jill E. Shea, Michael T. Seipp, Jeffrey T. Yap, Lance D. Burrell, David H. Lum, Jonathan R. Whisenant, G. Weldon Gilcrease, Courtney C. Cavalieri, Kaitrin M. Rehbein, Stephanie L. Cutler, Kajsa E. Affolter, Alana L. Welm, Bryan E. Welm, Courtney L. Scaife, Eric L. Snyder, Martin McMahon. Protective autophagy elicited by RAF®MEK®ERK inhibition suggests a treatment strategy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2183.

Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status.

BackgroundOncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028.MethodsThe effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo.ResultsThe co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone.ConclusionsThe synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status.

Treatment strategy for pancreatic cancer with simultaneous liver metastasis

The prognosis of pancreatic cancer is very poor, 40%-50% of patients have liver metastasis at the time of initial diagnosis, and only 15%-20% of patients have the chance of surgical resection. At present, there is no consensus on the treatment strategy of pancreatic cancer with simultaneous liver metastasis. Surgeons are still looking forward to surgical resection for patients with longer survival time. The application of neoadjuvant therapy and radiofrequency ablation may bring new breakthroughs in the treatment of pancreatic cancer with simultaneous liver metastasis. This article reviews the surgical, neoadjuvant and palliative treatment of pancreatic cancer with simultaneous liver metastasis. Key words: Pancreatic neoplasms; Liver; Neoplasm metastasis; Treatment outcome; Simultaneity

Diarylidenylpiperidones, H-4073 and HO-3867, Induce G2/M Cell-Cycle Arrest, Apoptosis and Inhibit STAT3 Phosphorylation in Human Pancreatic Cancer Cells.

Pancreatic cancer has a 5-year survival rate below 10% and the treatment options are limited. Signal transducer and activator of transcription (STAT3) is a constitutively expressed protein in human pancreatic cancers and is associated with their poor prognosis. Targeting of STAT3 signaling using novel therapeutic agents is a potential strategy for pancreatic cancer treatment. Diarylidenylpiperidone (DAP) compounds, such as H-4073 and HO-3867, have been shown to be STAT3 inhibitors in several human ovarian cancers. Particularly, HO-3867 is an N-hydroxypyrroline derivative of DAP that has targeted cytotoxicity toward cancer cells without affecting healthy cells. In the present study, we evaluated the anticancer efficacy of H-4073 and HO-3867 in a human pancreatic cell line (AsPC-1). We found that both the compounds exhibited potential cytotoxicity to AsPC-1 cells by inducing G2/M cell-cycle arrest, apoptosis, and cell death, by mitochondrial damage and inhibition of STAT3 phosphorylation. In summary, H-4073 and HO-3867 are cytotoxic to AsPC-1 cells and seem to act through similar mechanisms, including STAT3 inhibition, cell-cycle arrest, and apoptosis.