Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer.
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ABSTRACT:
SUBMITTER: Jones PH
PROVIDER: S-EPMC2364746 | biostudies-other | 2004 Jul
REPOSITORIES: biostudies-other
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Project description:Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.
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Project description:Antiangiogenic drug treatment inhibits tumor growth by decreasing blood supply, which can also reduce the delivery of other therapeutic agents. Presently, we investigated the effect of the vascular endothelial growth factor receptor tyrosine kinase inhibitor axitinib (AG-013736) on tumor vascular patency and chemotherapeutic drug uptake. Furthermore, the effect of axitinib on the antitumor activity of combination treatments with cyclophosphamide was examined.Prostate cancer PC-3 xenografts were used to evaluate the effect of axitinib treatment on tumor vascular morphology, fluorescent dye perfusion, hypoxia, and uptake of 4-hydroxycyclophosphamide, the active metabolite of the chemotherapeutic prodrug cyclophosphamide. Sequential or simultaneous schedules for axitinib and cyclophosphamide administration were evaluated in both PC-3 tumors and 9L gliosarcoma xenograft models.Axitinib monotherapy induced sustained growth stasis in PC-3 tumors in association with extensive apoptotic cell death. A substantial decrease in tumor vascular patency was observed, exemplified by a near complete loss of Hoechst 33342 perfusion and the absence of pimonidazole staining in the increasingly hypoxic tumors. Antitumor activity was significantly enhanced in both PC-3 and 9L tumors treated using an optimized schedule of sequential, intermittent axitinib-cyclophosphamide combination therapy despite a 40% to 70% decrease in tumor tissue uptake of 4-hydroxycyclophosphamide.In axitinib-cyclophosphamide combination therapy, enhanced anticancer activity can be achieved when the reduced tumor cell exposure to the cancer chemotherapeutic agent is compensated by antiangiogenesis-induced tumor cell starvation. This intrinsic antitumor effect was particularly evident in PC-3 tumor xenografts, where tumor blood flow deprivation dominates the overall therapeutic response.
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Project description:Primary pulmonary mucinous adenocarcinoma is an unusual histological type of non-small cell lung cancer and has a rare prevalence at a young age. There is no standard first-line therapy for advanced primary pulmonary mucinous adenocarcinoma in children and young adults-this study reports two rare cases of primary pulmonary mucinous adenocarcinoma with wild-type anaplastic lymphoma kinase and epidermal growth factor receptor (EGFR) genes. One is a 13-year-old boy (Case#1), and another is a 27-year-old male (Case#2). Both two cases were treated with antibiotics for suspected pulmonary infection. In our hospital, they were diagnosed with advanced primary pulmonary mucinous adenocarcinoma, the Eastern Cooperative Oncology Group (ECGO) performance status was three scores. We chose pembrolizumab and chemotherapy plus angiogenesis inhibitors for Case#1 and Case#2. The two patients' symptoms improved and presented with a partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria，the scores of ECOG performance status were two for Case#1 and one for Case#2. This study illustrates a promising outcome for advanced primary pulmonary mucinous adenocarcinoma with immunotherapy and chemotherapy plus angiogenesis inhibitors at a young age.
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Project description:Both malignant tumor growth and metastasis are dependent upon angiogenesis, a process of new blood vessel formation. Inhibition of this process by specific inhibitors might be able to control tumor growth and metastasis. Therefore, antiangiogenesis thereapy is considered a promising strategy and being studied worldwide. A wide variety of angiogenesis inhibitors have been identified and some of them are under clinical trials in the advanced patients with cancer including gastric cancer. This review summarizes the development and progress of angiogenesis inhibitors in recent decades, and discusses the future direction of antiangiogenesis research, and the potential antiangiogenic agents which are most likely to be translated into standard treatment for gastrointestinal cancer patients either alone or combined with other therapies.
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Project description:Angiogenesis is a hallmark of tumor development and metastasis and is now a validated target for cancer treatment. However, the survival benefits of antiangiogenic drugs have thus far been rather modest, stimulating interest in developing more effective ways to combine antiangiogenic drugs with established chemotherapies. This review discusses recent progress and emerging challenges in this field; interactions between antiangiogenic drugs and conventional chemotherapeutic agents are examined, and strategies for the optimization of combination therapies are discussed. Antiangiogenic drugs such as the anti-vascular endothelial growth factor antibody bevacizumab can induce a functional normalization of the tumor vasculature that is transient and can potentiate the activity of coadministered chemoradiotherapies. However, chronic angiogenesis inhibition typically reduces tumor uptake of coadministered chemotherapeutics, indicating a need to explore new approaches, including intermittent treatment schedules and provascular strategies to increase chemotherapeutic drug exposure. In cases where antiangiogenesis-induced tumor cell starvation augments the intrinsic cytotoxic effects of a conventional chemotherapeutic drug, combination therapy may increase antitumor activity despite a decrease in cytotoxic drug exposure. As new angiogenesis inhibitors enter the clinic, reliable surrogate markers are needed to monitor the progress of antiangiogenic therapies and to identify responsive patients. New targets for antiangiogenesis continue to be discovered, increasing the opportunities to interdict tumor angiogenesis and circumvent resistance mechanisms that may emerge with chronic use of these drugs.
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Project description:PurposeThe miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC).MethodsAn open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death.ResultsFifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%.ConclusionsThe combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785.
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Project description:The process of new blood vessel formation, or angiogenesis, has become an important target for therapeutic intervention in many cancers, including metastatic colorectal cancer (mCRC). The growth and metastasis of primary tumors is dependent upon their ability to acquire and maintain an adequate blood supply; however, angiogenesis in tumors is an irregular process leading to chaotic and hyperpermeable vessels that may result in increased intratumoral pressure and poor exchange of macromolecules and oxygen. It has been hypothesized that inhibition of angiogenesis in tumors can both impair the formation of new tumor blood vessels and possibly 'normalize' the existing tumor vasculature, causing a more efficient delivery of cytotoxic chemotherapies (CTs). Over the last decade, therapies that target vascular endothelial growth factor (VEGF) have become a component of treatment for several cancers. In particular, the combination of bevacizumab with established chemotherapeutic regimens for mCRC has been shown to improve overall and progression-free survival, as well as response rates, over CT alone. Agents that target various members of the VEGF family, as well as signaling by the VEGF receptors and their tyrosine kinase components, are currently under development and evaluation in clinical trials. Integration of these new therapies into the treatment of mCRC will ultimately increase the available therapeutic options for patients. Still, many challenges remain, including identifying and validating relevant biomarkers to guide the optimal use of antiangiogenesis agents.
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Project description:Antiangiogenesis therapy has been demonstrated to prolong the free survival with tolerable toxicity. However the efficacy of these drugs in overall survival (OS) remains controversial. This study was designed to assess the overall performance of antiangiogenesis therapy in improving the survival of ovary cancer (OC) patients.Electronic database of PubMed, Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched to identify relevant clinical randomized control trial (RCTs) assessing the therapeutic value of antiangiogenesis therapy in OC patients during 2011 to 2017. Additionally, abstracts of annual meetings were also conducted. Only English articles were considered. Progression free survival (PFS), OS, and objective response rate (ORR) were obtained from eligible RCTs. The HRs for time-to-event variables and ORs for dichotomous outcomes with their 95% CIs were used for this meta-analysis. All the statistical analyses were carried out by Stata 11.0 software using a fixed or random-models according to heterogeneity.A total of 15 RCTs including 9359 patients were recruited into this meta-analysis. Addition of antiangiogenic agents improved PFS (HR?=?0.71, 95% CI 0.62-0.81, P?<?.001), OS (HR?=?0.92, 95% CI 0.86-0.98, P?=?.008) and ORR (OR?=?1.74, 95% CI 1.27-2.39, P?=?.001) compared to placebo or chemotherapy alone in overall analysis. Antiangiogenic agents prolonged both PFS (HR?=?0.58, 95% CI 0.52-0.65, P?=?.000) and OS (HR=0.84, 95% CI 0.76-0.92, P?=?.000) in recurrent settings but only PFS in primary settings (HR?=?0.88, 95% CI 0.79-0.98, P?=?.020), longer PFS and OS in both platinum-sensitive recurrent patients (HR?=?0.56, 95% CI 0.48-0.64, P?=?.000, PFS; HR?=?0.86, 95% CI 0.76-0.98, P?=?.027, OS) as well as platinum-resistant recurrent cases (HR?=?0.54, 95% CI 0.41-0.71, P?=?.000, PFS; HR?=?0.84, 95% CI 0.71-0.98, P?=?.029, OS). Throughout therapy improved PFS (HR?=?0.66, 95% CI 0.57-0.76, P?<?.001) and OS (HR?=?0.89, 95% CI 0.83-0.96, P?=?.001). However the maintenance therapy of antiangiogenic agents was irrelevant to a longer PFS or OS.Based on the available studies, antiangiogenic agents play an important role in the survival of OC patients. More randomized controlled trials are needed to reach more convinced conclusion.
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Project description:Background:The objective of this study was to review the pharmacology, efficacy, and safety of palbociclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, for the management of advanced breast cancer (ABC). Methods:Pharmacokinetics and drug interactions associated with palbociclib are described. Recent clinical trial data are reviewed, including patient-reported outcomes and subgroup analyses. Results:Palbociclib is indicated in combination with an aromatase inhibitor as initial endocrine therapy (ET) or with fulvestrant for patients with disease progression following ET for hormone receptor positive, human epidermal growth factor receptor 2 negative ABC or metastatic breast cancer. Palbociclib inhibits cyclin-dependent kinases 4/6, resulting in a blockade of phosphorylation of the retinoblastoma protein, which hinders the activation of transcription factors involved in S-phase entry, thereby arresting cell cycle progression at G1 phase. The efficacy and safety of palbociclib in combination with ET was established in three randomized trials (PALOMA-1, -2, and -3); all studies met their primary endpoint of significantly prolonging investigator-assessed progression-free survival versus ET alone. Findings were similar in subgroup analyses of the three PALOMA studies. Palbociclib plus ET also maintained health-related quality of life (QoL) compared with ET alone in PALOMA-2 and -3. A long-term safety profile for palbociclib, up to 3?years, has been established. Neutropenia, the most common any-grade and grade 3 or higher adverse event associated with palbociclib, is consistent with the drug's mechanism of action and can be effectively managed with dose interruption, dose reduction, or delay in starting treatment cycles. Conclusions:Palbociclib in combination with ET improved progression-free survival and QoL in patients with ABC, including in several patient subgroups.
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Project description:Photothermal therapy (PTT) is a promising cancer treatment modality, but PTT generally requires direct access to the source of light irradiation, thus precluding its utility against disseminated, metastatic tumors. Here, we demonstrate that PTT combined with chemotherapy can trigger potent anti-tumor immunity against disseminated tumors. Specifically, we have developed polydopamine-coated spiky gold nanoparticles as a new photothermal agent with extensive photothermal stability and efficiency. Strikingly, a single round of PTT combined with a sub-therapeutic dose of doxorubicin can elicit robust anti-tumor immune responses and eliminate local as well as untreated, distant tumors in >85% of animals bearing CT26 colon carcinoma. We also demonstrate their therapeutic efficacy against TC-1 submucosa-lung metastasis, a highly aggressive model for advanced head and neck squamous cell carcinoma (HNSCC). Our study sheds new light on a previously unrecognized, immunological facet of chemo-photothermal therapy and may lead to new therapeutic strategies against advanced cancer.
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