Current Standard Chemotherapy Research Articles

PAMs inhibits monoamine oxidase a activity and reduces glioma tumor growth, a potential adjuvant treatment for glioma

BackgroundMonoamine oxidase (MAO) A catalyzes oxidative deamination of monoamine neurotransmitters and dietary amines and regulates brain development and functions. Recently, we showed that MAO A mediates the progression and migration of glioma and MAO A inhibitors reduce glioma cell growth. Glioblastoma (GBM) is a common and most malignant brain tumor which is difficult to treat. Temozolomide (TMZ) is the current standard chemotherapy for glioma, but tumors usually become resistant and recur. So far, no effective therapy for TMZ-resistant glioma is available. Natural plant antimicrobial solution (PAMs) is a Chinese herbal medicine which has been used for decades without toxicity and has multiple medical functions including anti- inflammatory effects. Here, we report the effects of PAMs on glioblastoma growth.MethodsThe growth of TMZ -sensitive (U251S),-resistant (U251R) human glioma cells, and mouse glioma cell line GL-26 were assessed by MTS colorimetric assay, colony formation, and cell migration assays.Male C57BL/6 mice were implanted subcutaneously or intracranial with luciferase-positive mouse glioma GL-26 cells and treated with vehicle; MAO A inhibitor clorgyline (10 mg/kg); TMZ (1 mg/kg); PAMs (48 mg/kg) alone or in combination with TMZ (1 mg/kg) for 14 days. At the end of the treatment, mice were sacrificed, MAO A catalytic activity in tumors was measured, and tumor sizes were determined by imaging and weight.ResultsThese results show that PAMs inhibits MAO A catalytic activity in all three glioma cell lines studied U251S, U251R, and GL-26. PAMs reduced glioma growth and has greater effects in combination with low dose of TMZ than PAMS or TMZ alone in all three cell lines as shown by MTS, colony formation, and cell migration assays. Using the subcutaneous or intracranial GL-26 glioma mouse model, PAMs reduced the tumor growth and MAO A activity, similar to the MAO A inhibitor clorgyline. Combining PAMs with non-toxic dose TMZ increased survival to a greater extent than those of PAMs or TMZ alone.ConclusionsThis is the first study which suggests that PAMs alone or co-administration with low doses of TMZ may be a potential adjuvant to reduce the toxicity of TMZ and to abrogate drug resistance for the effective treatment of glioma.

Abstract 3094: Development of a prognostic and predictive 32 gene signature for gastric cancer

Abstract Clinical staging at initial cancer diagnosis guides the use and timing of chemotherapy and radiation. However, current pretreatment stratification modalities for gastric cancer (GC) are inadequate and improved tools are needed. In addition, while adjuvant chemotherapy after surgery improves survival of resectable gastric cancer, few predictive biomarkers exist to select patients who might benefit from the current standard chemotherapy. To develop prognostic and/or predictive signatures that are clinically relevant for GC patients, we performed a pan-cancer analysis of somatic mutation of 6,681 patients with 19 different cancer types using the machine learning algorithm NTriPath and identified a 32-gene GC signature. To determine clinical utility of the 32-gene GC signature, we used expression of the 32-gene GC signature from 567 GC patients to discover genetic subtypes. We found that the 32-gene GC signature are prognostic and predictive of response to adjuvant 5-fluorouracil and platinum doublet and pembrolizumab. We further validated the preditive value of the 32-gene GC signature using an independent cohort with metastatic GC treated with Immune Checkpoint Blockades. Finally, we built a genetic-subtype based risk-scoring model to predict overall survival that was validated in three independent cohorts (n = 976). The risk score accurately predicted survival as a continuous function and was significantly associated with survival independent of TNM stage, age, tumor location and Lauren type. Taken together, the 32-gene driven genetic subtype and the genetic-subtype based risk score can guide the use of the current standard of care adjuvant chemotherapy regimen and/or immunotherapy for gastric cancer patients and should be confirmed in prospective clinical trials. Citation Format: Sunho Park, Jae-Ho Cheong, Sam C. Wang, ChangJin Hong, Matthew Porembka, Tae Hyun Hwang. Development of a prognostic and predictive 32 gene signature for gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3094.

Abstract 17: MBQ-167, a Rac/Cdc42 targeted therapeutic, in combination with paclitaxel for TNBC treatment

Abstract Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally advanced and metastatic cancer. While targeted therapies for TNBC are in various stages of development, current standard chemotherapies include taxanes such as paclitaxel and anthracycline agents. With the objective of specifically targeting invasive cancer, our group has been developing small-molecule inhibitors of the Rho GTPases Rac and Cdc42, which are known drivers of cancer cell invasion and metastasis. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively, and consequently inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, tumor growth, and metastasis (Humphries-Bickley et al., Mol Cancer Ther 2017). We found that in addition to blocking HER2-type breast cancer progression, MBQ-167 is also highly effective against TNBC cell and tumor growth, as well as metastasis in mouse models. The purpose of this study was to test the efficacy of MBQ-167 in combination with the current chemotherapeutic paclitaxel. We hypothesized that the combination of paclitaxel and MBQ-167 is a rational strategy to inhibit tumor growth and metastasis in TNBC. To test this hypothesis, we administered a nontoxic dosage of individual MBQ-167, paclitaxel, or combined MBQ-167 and paclitaxel to immunocompromised mice bearing mammary fat pad tumors from GFP-tagged MDA-MB-468 or MDA-MB-231 human TNBC cells. Tumor growth was monitored weekly and metastasis was quantified at the end of the study. Treatment with MBQ-167 and/or paclitaxel resulted in reduced tumor growth by 70-80% in both models. In the MDA-MB-231 model, MBQ-167 paralleled paclitaxel treatment with a modest benefit in combined therapy. However, in the epidermal growth factor receptor (EGFR)-positive TNBC model MDA-MB-468, MBQ-167 alone or in combination significantly reduced metastasis to the lungs and spleen, while paclitaxel alone increased metastasis to the liver, lungs, and spleen. These results show that MBQ-167 is a promising antimetastatic agent that can be effective in combination with current chemotherapeutic agents. Citation Format: Jean Ruiz-Calderon, Irmaris Lopez-Lopez, Ailed Cruz-Collazo, Suranganie Dharmawardhane. MBQ-167, a Rac/Cdc42 targeted therapeutic, in combination with paclitaxel for TNBC treatment [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 17.

Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: Safety and efficacy results.

10506 Background: Low-grade gliomas (LGGs) are the most common brain tumors among children. Pediatric LGGs are often not surgically resectable and tend to demonstrate relapsed/remitting courses with current standard chemotherapy regimens. Moreover, radiation is often avoided due to its associated neurocognitive and endocrinologic sequelae. However, in pediatric patients (pts) with BRAF V600-mutant LGG, dabrafenib monotherapy has demonstrated meaningful clinical activity and acceptable tolerability (Hargrave et al, Clin Cancer Res. 2019; NCT01677741). Here we report the efficacy and safety of dabrafenib + trametinib (D+T) combination therapy in pediatric pts with previously treated BRAF V600-mutant LGG. Methods: This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772). The limited dose-escalation (ESC) portion evaluated the D+T combination in pediatric pts ( < 18 y) with recurrent/refractory BRAF V600-mutated solid tumors that were naive to MAPK pathway–targeted therapy. This was followed by a tumor cohort expansion (EXP), and the D+T combination was evaluated in BRAF V600-mutant LGG pts at recommended dose levels. Efficacy was determined by both investigator and independent review using the RANO criteria (for gliomas). Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Results: Overall, 36 pediatric pts with LGG received D+T combination therapy (ESC, n = 16; EXP, n = 20); pooled efficacy data were available for both ESC and EXP, while LGG-specific safety data were available for EXP. At interim analysis (Aug 2019), 17 of the 20 pts in EXP remained on protocol therapy. Three pts withdrew/discontinued treatment because of AEs. Skin toxicity (95%) and pyrexia (75%) were the frequent AEs reported. No on-treatment deaths were reported. Across both ESC and EXP, the objective response rate (ORR) was 25% (95% CI, 12%–42%) per independent review (1 complete response [CR], 8 partial response [PR], 24 stable disease [SD], 2 progressive disease [PD], 1 unknown [UNK]) and 50% (95% CI, 33%–67%) per investigator review (2 CR, 16 PR, 17 SD, 1 UNK). However, ORR + SD was similar, with 92% and 97% of pts having SD or better per independent and investigator review, respectively. Conclusions: In pediatric pts with pretreated BRAF V600-mutant LGG, D+T combination therapy demonstrated clinical activity, with 92% of pts having SD or better by independent review using the RANO criteria. Pyrexia and skin toxicity were the common AEs; majority of these were low-grade and manageable. Clinical trial information: NCT02124772.

Nanostructured Lipid Carriers for Delivery of Chemotherapeutics: A Review.

The efficacy of current standard chemotherapy is suboptimal due to the poor solubility and short half-lives of chemotherapeutic agents, as well as their high toxicity and lack of specificity which may result in severe side effects, noncompliance and patient inconvenience. The application of nanotechnology has revolutionized the pharmaceutical industry and attracted increasing attention as a significant means for optimizing the delivery of chemotherapeutic agents and enhancing their efficiency and safety profiles. Nanostructured lipid carriers (NLCs) are lipid-based formulations that have been broadly studied as drug delivery systems. They have a solid matrix at room temperature and are considered superior to many other traditional lipid-based nanocarriers such as nanoemulsions, liposomes and solid lipid nanoparticles (SLNs) due to their enhanced physical stability, improved drug loading capacity, and biocompatibility. This review focuses on the latest advances in the use of NLCs as drug delivery systems and their preparation and characterization techniques with special emphasis on their applications as delivery systems for chemotherapeutic agents and different strategies for their use in tumor targeting.

Genetic polymorphisms and vincristine-induced peripheral neuropathy in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy.

Vincristine (VCR)-induced peripheral neuropathy (VIPN) is a common and life-long toxicity in lymphoma patients receiving current standard chemotherapy. The association between VIPN and genetic polymorphisms is largely unknown in adult lymphoma patients. To examine the possible relationship between known genetic polymorphisms in patients with pediatric acute lymphoblastic leukemia and incidence of VIPN in adult patients with B cell lymphoma, we examined CEP72 rs924607, ETAA1 rs17032980, MTNR1B rs12786200, CYP3A5 rs776746, rs7963521, and rs1045644 genetic polymorphisms in samples from 56 adult patients with B-cell lymphoma who received rituximab, cyclophosphamide, doxorubicin, VCR, and prednisone (R-CHOP) chemotherapy. Mutation analysis was performed by direct sequencing. The median age was 65years (range 30-79). The median cumulative dose of VCR was 12mg (range 2-16). VIPN was documented in 42 patients (75%), and 9 (16%) had grade 2-4 VIPN. Age, impaired glucose tolerance, number of cycles of R-CHOP, and VCR cumulative dose were not associated with incidence of VIPN. There was no association between the incidence of grade 2-4 or any grade VIPN and these six genetic polymorphisms. These results indicate that CEP72, MTNR1B, ETAA1, CYP3A5, rs7963521, and rs1045644 genetic polymorphisms are not associated with VIPN in patients with B-cell lymphoma who received R-CHOP.

The Tyrosine Phosphatase Shp2 Regulates Yapy357 Phosphorylation, And In Vivo Sensitivity To Cytotoxic Chemotherapy In Cholangiocarcinoma

Presenter: EeeLN Buckarma MD | Mayo Clinic, Rochester Background: Cancer of the biliary tract, cholangiocarcinoma (CCA), is increasing in incidence and has limited treatment options. In an attempt to further understand signaling pathways driving oncogenesis and impacting response to therapy we, and others, have identified altered activation of the transcriptional co-activator, Yes- associated protein (YAP) in CCA. Canonical regulatory pathways impacting YAP consist of serine kinases; however, more recently we have demonstrated a central role for tyrosine phosphorylation in regulating YAP function in CCA. Herein we explore the role of tyrosine phosphatases in regulating YAP tyrosine phosphorylation and sensitivity to current cytotoxic chemotherapy. Methods: Molecular studies utilized the human CCA cell lines HuCCT-1 and KMCH. Baseline tyrosine phosphatase levels were assessed by RT-PCR and immunoblot. YAP-interacting phosphatases were identified by co-immunoprecipitation. The selective tyrosine phosphatse inhibitors NSC87877 and SHP099 were utilized. Tyrosine phosphorylation was assessed by immunoblot. YAP transcriptional activity was evaluated by RT-PCR for YAP target genes. SHP2 levels were modulated utilizing knockout via a doxycycline-inducible CRISPR/Cas9 system. Enforced expression of SHP2 was explored utilizing catalytically active and dead constructs. YAP sub-cellular localization was assessed by immunofluorescence. Proliferation was evaluated by MTS assay and cell viability was assessed with Cell Titer-Glo. Cytotoxic agents’ gemcitabine and cisplatin were utilized for in vitro and in vivo studies. CCA xenografts (via mouse flank model) were generated with non-targeting small guide-bearing KMCH and sgSHP2-KMCH cells. Mice were treated with q3 day cytotoxic treatment x 3 weeks and tumors were evaluated by growth rate, weight and volume. Results: Profiling of tyrosine phosphatase levels by RT-PCR and immunoblot demonstrated higher levels in KMCH cells compared to HuCCT-1; notably the YAP-interacting phosphatase PTPN11 (SHP2) was elevated. Consistent with the anticipated function of the phosphatases, immunoblot demonstrated lower levels of tyrosine phosphorylated YAP (p-YAPY357) in KMCH cells compared to HuCCT-1. The role of SHP2 was further probed by incubation of KMCH and HuCCT-1 cells with NSC87877 which was associated with an increase in p-YAPY357 levels and YAP co-transcriptional activity. In addition, KMCH cells demonstrated increased YAP nuclear localization following incubation with NSC87877. The effects seen with YAP tyrosine phosphorylation were paralleled in doxycycline-inducible CRISPR/Cas9 sgSHP2-KMCH cells. In HuCCT1 cells overexpressing SHP2 (WT-SHP2), pYAPY357 levels and transcriptional activity were decreased, and the localization of YAP was shifted towards the cytoplasmic compartment. Expression of a phosphatase-dead construct (C459S-SHP2) had no demonstrable effect. A deletion-reconstitution approach utilizing induced sgSHP2-KMCH cells followed by reconstitution with expression of either wild-type or phosphatase-dead constructs was associated with a decrease in p-YAP357 levels, YAP transcriptional activity, and YAP baseline nuclear localization in wild-type alone. Increased cell death was observed in KMCH cells as compared the HuCCT-1 and sgSHP2-KMCH cells incubated with gemcitabine and cisplatin. In keeping with these observations, in vivo studies demonstrated that the sgSHP2-KMCH cell lines when compared to wild type, developed tumors with faster growth rates, and subsequently these tumors were less sensitive to the combination of gemcitabine and cisplatin therapy. Conclusion: The tyrosine phosphatase SHP2 regulates p-YAPY357 levels, YAP co-transcriptional activity, and in vivo sensitivity to current standard chemotherapy in cholangiocarcinoma.

Efficacy and Safety of Pembrolizumab in Patients with Refractory Advanced Biliary Tract Cancer: Tumor Proportion Score as a Potential Biomarker for Response.

PurposeThe current standard chemotherapy for advanced biliary tract cancer (BTC) has limited benefit, and novel therapies need to be investigated. Materials and MethodsIn this prospective cohort study, programmed death ligand-1 (PD-L1)–positive BTC patients who progressed on first-line gemcitabine plus cisplatin were enrolled. Pembrolizumab 200 mg was administered intravenously every 3 weeks. ResultsBetween May 2018 and February 2019, 40 patients were enrolled. Pembrolizumab was given as second-line (47.5%) or ≥ third-line therapy (52.5%). The objective response rate was 10% and 12.5% by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 and immune- modified RECIST (imRECIST) and median duration of response was 6.3 months. Among patients with progressive disease as best response, one patient (1/20, 5.0%) achieved complete response subsequently. The median progression-free survival (PFS) and overall survival (OS) were 1.5 months (95% confidence interval [CI], 0.0 to 3.0) and 4.3 months (95% CI, 3.5 to 5.1), respectively, and objective response per imRECIST was significantly associated with PFS (p < 0.001) and OS (p=0.001). Tumor proportion score ≥ 50% was significantly associated with higher response rates including the response after pseudoprogression (vs. < 50%; 37.5% vs. 6.5%; p=0.049). ConclusionPembrolizumab showed modest anti-tumor activity in heavily pretreated PD-L1–positive BTC patients. In patients who showed objective response, durable response could be achieved.

Distinct Gene Expression Profiles and Mutations Associate with Outcome in Younger Adults with De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) (Alliance)

Distinct Gene Expression Profiles and Mutations Associate with Outcome in Younger Adults with De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) (Alliance)

The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: clinical and preclinical investigations

ABSTRACTSystemic inflammatory responses including thrombocytosis, leukocytosis, or neutrophilia have gained attention as prognostic indicators in patients with various solid malignancies.current study, we aimed to investigate the clinical implications and underlying biological mechanism of the systemic inflammatory response in endometrial cancer. Clinical data from 900 patients with endometrial cancer were analyzed to investigate the association between pretreatment leukocytosis, thrombocytosis, and treatment outcome. Clinical samples, endometrial cancer cell lines, and a mouse model of endometrial cancer were used to examine the mechanisms responsible for systemic inflammatory response in endometrial cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and MDSCs. Then, we showed that pretreatment concurrent leukocytosis and thrombocytosis is associated with significantly shorter survival and decreased chemosensitivity among patients with endometrial cancer. In vitro and in vivo experiments revealed that tumor-derived G-CSF and G-CSF-mediated IL-6 production from the tumor microenvironment are involved in the development of leukocytosis and thrombocytosis in patients with endometrial cancer. Moreover, increased tumor-infiltrating MDSCs induced by tumor-derived G-CSF, MDSC-mediated T cell suppression, and MDSC-mediated cancer stem cell induction are responsible for progression and chemoresistance in this type of endometrial cancer. MDSC depletion using an anti-Gr-1 neutralizing antibody or inhibition of MDSC activity by celecoxib inhibited tumor growth and enhanced chemosensitivity in endometrial cancer displaying concurrent leukocytosis and thrombocytosis. In conclusion, Pretreatment concurrent leukocytosis and thrombocytosis are associated with significantly shorter survival and decreased chemosensitivity among patients with endometrial cancer. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy for these patients.

Survival of patients with metastatic HER2 positive gastro-oesophageal cancer treated with second-line chemotherapy plus trastuzumab or ramucirumab after progression on front-line chemotherapy plus trastuzumab

BackgroundThe role of continuing anti-HER2 therapy beyond progression on front-line therapy in patients with metastatic HER2 positive gastro-oesophageal cancer (GEC) is unclear. Continued chemotherapy plus trastuzumab (CT) has never been compared with the current standard second-line treatment, chemotherapy plus ramucirumab (CR).MethodsThe Flatiron Health electronic health record derived database, a nationwide database comprising patient-level structured and unstructured data, curated via technology-enabled abstraction, was reviewed for patients with metastatic HER2 positive GEC who received first-line CT, followed by second-line CT or CR. Survival from second-line therapy (SST) and time to next therapy or death (TTNTD) were compared using Kaplan-Meier curves and logrank analysis.Results133 patients with metastatic HER2 positive GEC who received first-line CT were identified. 32 received second-line CR and 101 received CT. Median SST for patients treated with CT versus CR was 10.2 months (IQR 5.1–20.8) and 6.8 months (IQR 2.4–20.2), respectively (p=0.29). Median TTNTD for second-line CT versus CR was 4.9 months (IQR 2.8–9.8) and 5.1 months (IQR 2.3–7.5), respectively (p=0.65). Patients who received second-line CT were more likely to receive a multiagent chemotherapy backbone (76% vs 3%, p≤0.001).ConclusionsThis analysis showed no significant difference in SST for patients treated with second-line CT versus CR. Further studies are needed to clarify the role of trastuzumab in the second line, especially in patients with confirmed retention of HER2 positivity following progression.

Phase I/II Study: Experience with the Late Onset of Acute Pancreatitis after the Start of Chemotherapy with Gemcitabine Plus nab-Paclitaxel for Metastatic Pancreatic Cancer

Gemcitabine plus nab-paclitaxel is the current standard chemotherapy for patients with metastatic pancreatic cancer. We conducted a phase I/II study in Japan, in which high response rates and manageable toxicity were observed. In this study, two patients were reported as experiencing pancreatitis due to chemotherapy. In general, pancreatitis is sometimes observed when the tumor involves the pancreatic duct, and the onset is observed before the diagnosis or at the initial stage. The onset of pancreatitis in these cases was unique and observed after the start of chemotherapy. Pancreatitis may be induced by the alleviation of stenosis of the pancreatic duct associated with tumor shrinkage.

Glaucocalyxin A reverses EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma

Metastatic osteosarcoma usually has an unsatisfactory response to the current standard chemotherapy and causes poor prognosis. Currently, epithelial-mesenchymal transition (EMT) is reported as a critical event in osteosarcoma metastasis. Glaucocalyxin A, a bioactive ent-kauranoid diterpenoid, exerts anti-cancer effect on osteosarcoma by inducing apoptosis in previous study. However, the effect of Glaucocalyxin A on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the potential mechanisms of Glaucocalyxin A on EMT and metastasis of osteosarcoma. We found that Glaucocalyxin A inhibited migration and invasion of MG-63 and 143B cells. Moreover, Glaucocalyxin A increased the protein and mRNA levels of E-cadherin and decreased the protein and transcription expression of N-cadherin, Vimentin. Glaucocalyxin A also inhibited the protein and mRNA levels of EMT-associated transcription factor including Snail and Slug. Furthermore, Glaucocalyxin A inhibited transforming growth factor-β1 (TGF-β1)-induced migration, invasion and EMT of low-metastatic osteosarcoma U2OS cells. Glaucocalyxin A inhibited TGF-β-induced phosphorylation of Smad 2/3 in osteosarcoma U2OS cells. Finally, we established transplanted metastatic models of highly metastatic osteosarcoma 143B cells. Glaucocalyxin A inhibited lung metastasis in vivo. Interestingly, Glaucocalyxin A increased the protein expression of E-cadherin and reduced the protein expression of N-cadherin and Vimentin. Glaucocalyxin A inhibited the protein expression of Snail and Slug in vivo. In summary, this study demonstrated that Glaucocalyxin A inhibited EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Therefore, Glaucocalyxin A might be a promising candidate against the metastasis of human osteosarcoma.

Identification of MRP4/ABCC4 as a Target for Reducing the Proliferation of Pancreatic Ductal Adenocarcinoma Cells by Modulating the cAMP Efflux.

Pancreatic cancer is one of the most lethal types of tumors with no effective therapy available; is currently the third leading cause of cancer in developed countries; and is predicted to become the second deadliest cancer in the United States by 2030. Due to the marginal benefits of current standard chemotherapy, the identification of new therapeutic targets is greatly required. Considering that cAMP pathway is commonly activated in pancreatic ductal adenocarcinoma (PDAC) and its premalignant lesions, we aim to investigate the multidrug resistance-associated protein 4 (MRP4)-dependent cAMP extrusion process as a cause of increased cell proliferation in human PDAC cell lines. Our results from in silico analysis indicate that MRP4 expression may influence PDAC patient outcome; thus, high MRP4 levels could be indicators of poor survival. In addition, we performed in vitro experiments and identified an association between higher MRP4 expression levels and more undifferentiated and malignant models of PDAC and cAMP extrusion capacity. We studied the antiproliferative effect and the overall cAMP response of three MRP4 inhibitors, probenecid, MK571, and ceefourin-1 in PDAC in vitro models. Moreover, MRP4-specific silencing in PANC-1 cells reduced cell proliferation (P < 0.05), whereas MRP4 overexpression in BxPC-3 cells significantly incremented their growth rate in culture (P < 0.05). MRP4 pharmacological inhibition or silencing abrogated cell proliferation through the activation of the cAMP/Epac/Rap1 signaling pathway. Also, extracellular cAMP reverted the antiproliferative effect of MRP4 blockade. Our data highlight the MRP4-dependent cAMP extrusion process as a key participant in cell proliferation, indicating that MRP4 could be an exploitable therapeutic target for PDAC. SIGNIFICANCE STATEMENT: ABCC4/MRP4 is the main transporter responsible for cAMP efflux. In this work, we show that MRP4 expression may influence PDAC patient outcome and identify an association between higher MRP4 expression levels and more undifferentiated and malignant in vitro models of PDAC. Findings prove the involvement of MRP4 in PDAC cell proliferation through a novel extracellular cAMP mitogenic pathway and further support MRP4 inhibition as a promising therapeutic strategy for PDAC treatment.

A Therapeutic Strategy for Chemotherapy-Resistant Gastric Cancer via Destabilization of Both β-Catenin and RAS.

Treatment of advanced gastric cancer patients with current standard chemotherapeutic agents frequently results in resistance, leading to poor overall survival. However, there has been no success in developing strategies to overcome it. We showed the expression levels of both β-catenin and RAS were significantly increased and correlated in tissues of 756 gastric cancer (GC) patients and tissues of primary- and acquired-resistance patient-derived xenograft tumors treated with 5-fluorouracil and oxaliplatin modulated with leucovorin (FOLFOX). On the basis of our previous studies, where small molecules to suppress colorectal cancer (CRC) via degrading both β-catenin and RAS were developed, we tested the effectiveness of KYA1797K, a representative compound functioning by binding axin, in the growth of GC cells. The efficacy test of the drugs using gastric tumor organoids of Apc1638N mice showed that the CD44 and ALDH1A3 cancer stem cell markers were induced by FOLFOX, but not by KYA1797K. KYA1797K also efficiently suppressed tumors generated by re-engrafting the FOLFOX-resistant patient-derived xenograft (PDX) tumors, which also showed resistance to paclitaxel. Overall, the small-molecule approach degrading both β-catenin and RAS has potential as a therapeutic strategy for treating GC patients resistant to current standard chemotherapies.

Role of Dicer in regulating oxaliplatin resistance of colon cancer cells

Colorectal cancer (CRC) is a major health problem due to its high mortality rate. The incidence of CRC is increasing in young individuals. Oxaliplatin (OXA) is an approved third-generation drug and is used for first-line chemotherapy in CRC. Although current standard chemotherapy improves the overall survival of CRC patients, an increasing number of reports of OXA resistance in CRC therapy indicates that resistance has become an urgent problem in clinical applications. Dicer is a critical enzyme involved in miRNA maturation. The expression of Dicer has been reported to be involved in the resistance to various drugs in cancer. In the present study, we aimed to investigate the role of Dicer in OXA resistance in CRC. We found that OXA treatment inhibited Dicer expression through decreasing the protein stability. OXA-induced Dicer protein degradation occurred through both proteasomal and lysosomal proteolysis, while the CHIP E3 ligase was involved in OXA-mediated Dicer ubiquitination and degradation. We established stable OXA-resistant clones from CRC cells, and observed that the CHIP E3 ligase was decreased, along with the increased Dicer expression in OXA-resistant cells. Knockdown of Dicer resensitized CRC cells to OXA treatment. In this study, we have revealed the role of miRNA biogenesis factors in OXA resistance in CRC cells.

787TiP - A phase III study of adjuvant docetaxel, capecitabine and oxaliplatin triplet vs capecitabine and oxaliplatin doublet in patients with curatively resected stage IIIB or IV(M0) (AJCC 6th ed) gastric adenocarcinoma (TRIUMPH, KCSG ST14-05)

Background: In stage IIIB or IV(M0) (by AJCC 6th edition) gastric cancer (GC), recurrence rate is higher than 50% even with curative D2 surgery and current standard adjuvant chemotherapy with capecitabine and oxaliplatin (XO) or S-1. Accordingly, more effective treatment is needed to reduce recurrence rate in these far advanced GCs. Our previous phase II study of adjuvant chemotherapy in stage IIIB or IV(M0) GC (Yoon S, et al. Gastric Cancer. 2017;20:182) suggested that docetaxel-containing triplet was safe and might be better in terms of recurrence-free survival (RFS) when compared with historic data of fluoropyrimidine plus platinum or fluoropyrimidine alone. Based on this background, a phase III randomized study to evaluate adjuvant docetaxel, capecitabine and oxaliplatin (DXO) triplet vs current standard XO in patients (pts) with curatively resected stage IIIB or IV(M0) GC has been initiated (NCT01935778). Trial design: Since October 2013, pts with curatively resected stage IIIB or IV(M0) gastric or gastroesophageal junction adenocarcinoma have been recruited from 6 sites in Korean Cancer Study Group (KCSG). Other key eligibility criteria include ECOG performance status 0-1, age of 20-75 years, D2 surgery, and adequate organ functions. Three to 8 weeks after surgery, pts are randomized 1:1 in open label to adjuvant DXO arm vs XO arm. Stratification factors for randomization include pathologic stage (IIIB vs IV(M0)) and extent of gastrectomy (total vs subtotal). In DXO arm, pts receive docetaxel 60 mg/m2 i.v. on day 1, capecitabine 800 mg/m2 p.o. twice daily on days 1-14, and oxaliplatin 100 mg/m2 i.v. on day 1, every 3 weeks for 6 cycles; in XO arm, pts receive capecitabine 1000 mg/m2 p.o. twice daily on days 1-14, and oxaliplatin 130 mg/m2 i.v. on day 1, every 3 weeks for 8 cycles. Primary endpoint is 3-year RFS rate. Secondary endpoints include overall survival and safety. With power of 80% and two-sided α level of 5%, 183 events are required to detect 15% difference in 3-year RFS rate, i.e., 50% in DXO arm vs 35% in XO arm (HR = 0.66). With 10% of drop-out rate, target enrollment is 286 subjects. Clinical trial identification: NCT01935778. Legal entity responsible for the study: Asan Medical Center. Funding: Boryung. Disclosure: M-H. Ryu: Consultant, Honoraria: DAE HWA Pharmaceutical, Bristol-Myers Squibb, Ono pharmaceutical. K-W. Lee: Research funding: Macrogenics, MSD, Green Cross Crop., ASLAN Pharmaceuticals, AstraZeneca/MedImmune, Five Prime Therapeutics, LSK BioPharma, Merck KGaA, Array BioPharma, Pharmacyclics, Pfizer, ONO Pharmaceuticals. M.H. Lee: Research funding: CJ Healthcare, Yuhan. Y-K. Kang: Consultant: Ono, BMS, Taiho, Roche, Lilly, Blueprint, Taiho, Daehwa, LSK Biopharma. All other authors have declared no conflicts of interest.

Serum expression level of IL-6 at the diagnosis time contributes to the long-term prognosis of SCLC patients.

Cytokines are vital mediators involved in tumor immunity. We aimed to explore whether the expression levels of IL-1β, TNF-α and IL-6 have impacts on prognosis of SCLC patients. In this study, we concluded 707 non-operable SCLC patients at stage III or IV into this study and analyzed the relationships between interleukins and OS/PFS by cox regression analysis and Kaplan-Meier analysis (log-rank test). As a result, under current standard chemotherapy, SCLC patients with higher IL-6 expression level had a shortened OS compared with those with normal level (HR: 0.381, 95%CI: 0.177-0.822, p=0.014). Furthermore, IL-6 expression level contributed mostly to patients without a smoking history. Non-smoking patients with a high IL-6 level showed a 6 months shortened OS than those with normal IL-6 level (10.50 vs 16.90 months, p=0.003 by Log-Rank test in Kaplan-Meier analysis). IL-6 had no obvious impacts on first-line PFS in these SCLC patients. To conclude, IL-6 acts as an independent factor of long-term prognosis of SCLC patients under current therapy.

Pooled analysis of the reports of carfilzomib/ixazomib combinations for relapsed/refractory multiple myeloma.

We sought to evaluate the activity and safety of carfilzomib-/ixazomib-containing combinations for patients with relapsed/refractory multiple myeloma (RRMM). We searched published reports including carfilzomib-/ixazomib-containing combinations for RRMM. Finally, we identified 11 prospective studies covering 2845 relapsed/refractory patients. Carfilzomib- and ixazomib-containing combinations respectively resulted in an impressive overall response rate (ORR 77 vs. 64%, P = 0.14), very good partial response or better (≥ VGPR 48 vs. 21%, P = 0.001), complete response or better (≥ CR 14 vs. 7%, P = 0.23), and clinical benefit rate (CBR 84 vs. 59%, P = 0.0002). Subgroup analysis showed that the carfilzomib (CFZ) +lenalidomide (LEN) + dexamethasone (DEX) triplet regimen resulted into similar response outcomes to those from CFZ + DEX doublet regimen in ORR (77 vs. 78%, P = 0.91), ≥VGPR (50 vs. 53%, P = 0.84), and ≥ CR (13 vs. 12%, P = 0.96) analysis in these previously heavily pretreated population. And, there were no statistically significant differences between IXA + LEN + DEX triplet regimen and CFZ + LEN + DEX triplet regimen in ORR (85 vs. 78%, P = 0.55), ≥ VGPR (37 vs. 53%, P = 0.19), and ≥ CR (18 vs. 12%, P = 0.70) analysis. There were favorable trend towards proteasome inhibitors (PIs) + IMiDs + DEX in comparison with PIs + alkylating agent + Dex in ORR (79 vs 49%, P < 0.00001), ≥ VGPR analysis (36 vs. 16%, P = 0.008), and ≥ CR (16 vs. 3%, P < 0.00001). Compared with current standard chemotherapy, carfilzomib containing combinations clearly improved overall survival (HR, 0.79; P = 0.01), progression free survival (HR, 0.61; P = 0.0001). Carfilzomib-/ixazomib-containing combinations produced clinical benefit for patients with R/RMM. PIs + IMiDs + DEX triplet regimens could be good options for such relapsed/refractory patients.

Role of Platinum in Early-Stage Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is both a clinically and genomically heterogeneous disease, with distinct molecular subtypes; however, most epidemiologic and clinical studies to date have defined it under a "one disease" umbrella. This is an important point, since one therapeutic approach for all TNBCs is unlikely to be successful given the underlying biological diversity. In this review, we explore the role of platinums in the treatment of TNBC, as well as the potential for biomarkers to predict patient response to these agents. The results of neoadjuvant TNBC trials, with addition of platinum to anthracycline/taxane-based chemotherapies, have been very encouraging given increases in pathologic complete response (pCR) rates. However, we do not have any evidence yet that these agents would lead to improvement in disease-free and overall survival. Moreover, addition of platinums increases toxicity and can compromise current standard chemotherapy doses, which further impedes their use in all TNBC patients. Therefore, the addition of platinums to standard chemotherapy should be used with caution and in discussion with patients after a careful assessment of risks and benefits. Clinical trials addressing the role of platinums in TNBC further remain of significant value.