Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer.
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ABSTRACT:
SUBMITTER: Dineen SP
PROVIDER: S-EPMC2848888 | biostudies-literature | 2010 Apr
REPOSITORIES: biostudies-literature
Publications
Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer.
Dineen Sean P SP Roland Christina L CL Greer Rachel R Carbon Juliet G JG Toombs Jason E JE Gupta Puja P Bardeesy Nabeel N Sun Haizhou H Williams Noelle N Minna John D JD Brekken Rolf A RA
Cancer research 20100323 7
Failure of chemotherapy in the treatment of pancreatic cancer is often due to resistance to therapy-induced apoptosis. A major mechanism for such resistance is the expression and activity of inhibitors of apoptosis proteins (IAP). Smac (second mitochondria-derived activator of caspase) is a mitochondrial protein that inhibits IAPs. We show that JP1201, a Smac mimetic, is a potent enhancer of chemotherapy in robust mouse models of pancreatic cancer. Combination of JP1201 with gemcitabine reduced ...[more]
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Project description:DNA damaging therapies can spur the formation of therapy-related cancers, due to mis-repair of lesions they create in non-cancerous cells. This risk may be amplified in patients with impaired DNA damage responses. We disabled key DNA damage response pathways using genetic and pharmacological approaches, and assessed the impact of these deficiencies on the mutagenicity of chemotherapy drugs or the "Smac mimetic" GDC-0152, which kills tumor cells by targeting XIAP, cIAP1 and 2. Doxorubicin and cisplatin provoked mutations in more surviving cells deficient in ATM, p53 or the homologous recombination effector RAD51 than in wild type cells, but suppressing non-homologous end joining (NHEJ) by disabling DNA-PKcs prevented chemotherapy-induced mutagenesis. Vincristine-induced mutagenesis required p53 and DNA-PKcs but was not affected by ATM status, consistent with it provoking ATM-independent p53-mediated activation of caspases and CAD, which creates DNA lesions in surviving cells that could be mis-repaired by NHEJ. Encouragingly, GDC-0152 failed to stimulate mutations in cells with proficient or defective DNA damage response pathways. This study highlights the elevated oncogenic risk associated with treating DNA repair-deficient patients with genotoxic anti-cancer therapies, and suggests a potential advantage for Smac mimetic drugs over traditional therapies: a reduced risk of therapy-related cancers.
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Project description:Ovarian cancer is the most lethal gynecological cancer in the US. Standard treatment consists of surgery followed by chemotherapies relying on apoptotic tumor cell death. Most women with advanced stage disease will relapse, suggesting that this disease is characterized by primary and acquired resistance to chemotherapy, and novel approaches to treatment are greatly needed. Low Caspase 8 expression levels in ovarian cancers correlate with resistance to apoptotic chemotherapy, and a subpopulation of patients with low Caspase 8 levels exhibit poorer overall survival after standard-of-care treatment. We hypothesized that low Caspase 8 function reduces the ability of cancer cells to undergo apoptosis when exposed to standard chemotherapy and that second mitochondria-derived activator of caspases (Smac)-mimetics could increase cell death in combination with chemotherapy. Here we show that combination treatment with a Smac-mimetic can target tumor cells with low Caspase 8 and induce necroptotic cell death. We investigated the in vitro effect of Smac-mimetic added to carboplatin and paclitaxel treatment of ovarian cancer cells expressing wild type and low Caspase 8 levels, which resulted in a 2-4-fold enhancement of cell death. Mice bearing subcutaneous or intraperitoneal ovarian xenografts showed greater aggressiveness of Caspase 8-deficient versus wild-type tumors; combined in vivo treatment with chemotherapy and Smac-mimetic resulted in >50% decrease in low Caspase 8 xenograft growth, as well as significantly enhanced overall survival, especially when given simultaneously with paclitaxel. Surprisingly, Smac-mimetic on the same day as carboplatin decreased mouse survival compared to when it was given on a sequential day of treatment. The antagonism was associated with a decrease in DNA damage markers, emphasizing the importance of optimizing timing of drug administration. Clinical validation of such approaches is needed to increase the effectiveness of current standard ovarian cancer treatment.
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Project description:BackgroundThe role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment.MethodsPatients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response.ResultsWe identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014).ConclusionCA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.
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Project description:BackgroundOvarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and the sigma-2 ligand portion of the conjugate facilitates cancer selectivity. The effector portion of the conjugate is expected to synergize with cisplatin chemotherapy and the cancer selectivity is expected to reduce putative off-target toxicities.MethodsOvarian cancer cell lines were treated with cisplatin alone, SW IV-134 alone and a combination of the two drugs. Treatment efficacy was determined using luminescent cell viability assays. Caspase-3/7, - 8 and - 9 activities were measured as complementary indicators of death pathway activation. Syngeneic mouse models and patient-derived xenograft (PDX) models of human ovarian cancer were studied for response to SW IV-134 and cisplatin monotherapy as well as combination therapy. Efficacy of the therapy was measured by tumor growth rate and survival as the primary readouts. Potential drug related toxicities were assessed at necropsy.ResultsThe combination treatment was consistently superior in multiple cell lines when compared to the single agents in vitro. The expected mechanism of tumor cell death, such as caspase activation, was confirmed using luminescent and flow cytometry-based assay systems. Combination therapy proved to be superior in both syngeneic and PDX-based murine models of ovarian cancer. Most notably, combination therapy resulted in a complete resolution of established tumors in all study animals in a patient-derived xenograft model of ovarian cancer.ConclusionsThe addition of SW IV-134 in combination with cisplatin chemotherapy represents a promising treatment option that warrants further pre-clinical development and evaluation as a therapy for women with advanced ovarian cancer.
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Project description:Zinc levels have been correlated with cancer risk, although the role of zinc and zinc transporters in cancer progression is largely unknown. We recently found that a zinc transporter, ZIP4, is overexpressed in pancreatic cancer. In this study, we further deciphered the role that ZIP4 plays in a pancreatic cancer mouse model by silencing ZIP4.ZIP4 stable silencing was established in pancreatic cancer cell lines ASPC-1 (ASPC-shZIP4) and BxPC-3 (BxPC-shZIP4) by short hairpin RNA using retrovirus vectors. The stable cells were characterized in vitro and in vivo using a nude mouse xenograft model.Silencing of ZIP4 was associated with decreased cell proliferation, migration, and invasion. Both ASPC-shZIP4 and BxPC-shZIP4 cells showed a significant reduction in tumor volume and weight in the s.c. model, and decreased primary tumor weight in the orthotopic model compared with the vector control cells (ASPC-shV and BxPC-shV). Silencing of ZIP4 also caused reduced incidence of tumor metastasis in the mice and downsized the tumor grade. More importantly, silencing of ZIP4 significantly increased the survival rate of nude mice with orthotopic xenografts (P = 0.005). All ASPC-shZIP4-injected mice (100%) remained alive up to 32 days after tumor implantation, whereas only 30% of the ASPC-shV mice were alive at the same time point. CyclinD1 expression was decreased in the ASPC-shZIP4 xenografts.These results identify a previously uncharacterized role of ZIP4 in pancreatic cancer progression, and indicate that knocking down ZIP4 by short hairpin RNA might be a novel treatment strategy for pancreatic cancers with ZIP4 overexpression.
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Project description:BackgroundChemotherapy is the standard treatment for breast cancer; however, the response to chemotherapy is disappointingly low. Here, we investigated the alternative therapeutic efficacy of novel combination treatment with necroptosis-inducing small molecules to overcome chemotherapeutic resistance in tyrosine aminoacyl-tRNA synthetase (YARS)-positive breast cancer.MethodsPre-chemotherapeutic needle biopsy of 143 invasive ductal carcinomas undergoing the same chemotherapeutic regimen was subjected to proteomic analysis. Four different machine learning algorithms were employed to determine signature protein combinations. Immunoreactive markers were selected using three common candidate proteins from the machine-learning algorithms and verified by immunohistochemistry using 123 cases of independent needle biopsy FFPE samples. The regulation of chemotherapeutic response and necroptotic cell death was assessed using lentiviral YARS overexpression and depletion 3D spheroid formation assay, viability assays, LDH release assay, flow cytometry analysis, and transmission electron microscopy. The ROS-induced metabolic dysregulation and phosphorylation of necrosome complex by YARS were assessed using oxygen consumption rate analysis, flow cytometry analysis, and 3D cell viability assay. The therapeutic roles of SMAC mimetics (LCL161) and a pan-BCL2 inhibitor (ABT-263) were determined by 3D cell viability assay and flow cytometry analysis. Additional biologic process and protein-protein interaction pathway analysis were performed using Gene Ontology annotation and Cytoscape databases.ResultsYARS was selected as a potential biomarker by proteomics-based machine-learning algorithms and was exclusively associated with good response to chemotherapy by subsequent immunohistochemical validation. In 3D spheroid models of breast cancer cell lines, YARS overexpression significantly improved chemotherapy response via phosphorylation of the necrosome complex. YARS-induced necroptosis sequentially mediated mitochondrial dysfunction through the overproduction of ROS in breast cancer cell lines. Combination treatment with necroptosis-inducing small molecules, including a SMAC mimetic (LCL161) and a pan-BCL2 inhibitor (ABT-263), showed therapeutic efficacy in YARS-overexpressing breast cancer cells.ConclusionsOur results indicate that, before chemotherapy, an initial screening of YARS protein expression should be performed, and YARS-positive breast cancer patients might consider the combined treatment with LCL161 and ABT-263; this could be a novel stepwise clinical approach to apply new targeted therapy in breast cancer patients in the future.
| S-EPMC7687715 | biostudies-literature