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CD8+ T-Cell Mediated Charge of HIV-1 in the Unique Cohort Along with Low Virus-like A lot.
001) and a comparable released docetaxel concentration (P=0.43). Plasma AUCinf was 27% higher (P=0.001) and Cmax was 91% lower (P less then 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 x 109/L) compared to CPC634 (4.30 x 109/L; P less then 0.001). CONCLUSION Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared to conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma Cmax of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase 2 efficacy trial of CPC634 is currently ongoing. Copyright ©2020, American Association for Cancer Research.PURPOSE Although taxane-based therapy is standard treatment for advanced gastric cancer (GC), a majority of patients exhibit intrinsic resistance to taxanes. Here, we aim to identify the molecular basis of taxane resistance in GC. EXPERIMENTAL DESIGN we performed a post-hoc analysis of the TAX-325 clinical trial and molecular interrogation of GC cell lines to assess the benefit of docetaxel in diffuse (DIF-GC) vs intestinal (INT-GC) GC. We assessed drug-induced microtubule stabilization in GC cells and in biopsies of GC patients treated with taxanes. We performed transcriptome analysis in taxane-treated GC cells and patients to identify molecular drivers of taxane resistance. RESULTS DIF-GC patients did not derive a clinical benefit from taxane treatment suggesting intrinsic taxane resistance. DIF-GC cell lines displayed intrinsic resistance specific to taxanes due to impaired drug-induced microtubule stabilization, in the absence of tubulin mutations or decreased drug accumulation. Using taxane-treated GC patient biopsies, we demonstrated that absence of drug-target engagement was correlated with clinical taxane resistance. Taxane-sensitive cell lines displayed faster microtubule dynamics at baseline, implicating proteins that regulate cytoskeletal dynamics in intrinsic taxane resistance. Differential gene expression analysis of untreated and docetaxel-treated GC lines and patient samples identified kinesins to be associated with taxane sensitivity in vitro and in patient samples. CONCLUSION our data reveal that taxane-resistance is more prevalent in patients with DIF-GC, support assessment of drug-target engagement as a early read-out of taxane clinical efficacy, and encourage the investigation of kinesins and other microtubule-associated proteins as potentially targetable mediators of taxane resistance in GC. Copyright ©2020, American Association for Cancer Research.PURPOSE Brain involvement occurs in majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation. EXPERIMENTAL DESIGN This study examined circulating BRAF, NRAS and c-KIT mutations in melanoma patients with active brain metastases receiving PD-1 inhibitor-based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analysed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/ml plasma). check details RESULTS Of a total of 72 patients; 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume (p less then 0.01). Undetectable ctDNA on-therapy was associated with extracranial response (p less then 0.01) but not intracranial response. The median overall survival in patients with undetectable (n = 34) versus detectable (n = 38) ctDNA at baseline was 39.2 versus 10.6 months (HR 0.51 [95% CI 0.28 - 0.94], p = 0.03) and on-therapy was 39.2 versus 9.2 months (HR 0.32 [95% CI 0.16 - 0.63], p less then 0.01). CONCLUSIONS ctDNA remains a strong prognostic biomarker in melanoma patients with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma. Copyright ©2020, American Association for Cancer Research.PURPOSE Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. EXPERIMENTAL DESIGN Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy. RESULTS Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the anti-diabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. CONCLUSIONS AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer. Copyright ©2020, American Association for Cancer Research.
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