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Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways. Although it is well-established that concurrent EGFR and Src inhibition exert these antineoplastic properties through direct inhibition of mitogenic pathways in tumor cells, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In this study, we demonstrate in both orthotopic tumor xenograft and (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, increases microvessel density, and prevents tissue fibrosis . Furthermore, the stromal changes induced by parallel EGFR and Src pathway inhibition resulted in improved overall survival in PKT mice when combined with gemcitabine. As a phase I clinical trial utilizing concurrent EGFR and Src inhibition with gemcitabine has recently concluded, these data provide timely translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance. IMPLICATIONS: These findings demonstrate that Src/EGFR inhibition targets STAT3, remodels the tumor stroma, and results in enhanced delivery of gemcitabine to improve overall survival in a mouse model of PDAC.
©2020 American Association for Cancer Research.
PURPOSE - Addition of either nab-paclitaxel or erlotinib to gemcitabine to treat advanced pancreatic cancer has demonstrated overall survival benefit. This study was conducted to evaluate the tolerability and safety of combining all three drugs and assess preliminary evidence of efficacy.
METHODS - In this open-label, phase 1b study, patients with previously untreated, advanced pancreatic cancer were treated in 28-day cycles with intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15, and once daily oral erlotinib. A standard "3 + 3" design was used. Dose level 1 (DL1) for gemcitabine (mg/m(2))/nab-paclitaxel (mg/m(2))/erlotinib (mg) was 1000/125/100, respectively, with de-escalation to DL-1 (1000/100/100), DL-2b (1000/75/100), and DL-3 (1000/75/75). The maximum tolerated dose (MTD) was defined by occurrence of dose-limiting toxicity (DLT) in ≤1 of six patients within the first cycle. Efficacy was assessed with CT scans performed at two-cycle intervals.
RESULTS - Nineteen patients were enrolled. DLTs occurred in two patients at DL1, three patients at DL-1, two patients at DL-2b, and one patient at DL-3. The MTD for the combination of gemcitabine/nab-paclitaxel/erlotinib was DL-3 (1000/75/75). In analyses of efficacy among 14 evaluable patients, partial responses were observed in four of six patients at DL1, one of two patients at DL-2b, and two of six patients at DL-3.
CONCLUSION - The addition of erlotinib to gemcitabine and nab-paclitaxel is not tolerable at standard single-agent dosing of all drugs. However, significant clinical activity was noted, even at DL-3. Further study of the combination will need to incorporate reduced dosing.
BACKGROUND & AIMS - A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance.
METHODS - Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density.
RESULTS - STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase.
CONCLUSIONS - Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.
OBJECTIVE - To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.
DESIGN - A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954).
SETTING - 57 sites in the United States and Puerto Rico.
PATIENTS - Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors.
INTERVENTION - Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.
MEASUREMENTS - Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.
RESULTS - Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.
LIMITATION - The trial was open-label, and ritonavir was not provided.
CONCLUSION - Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.
PRIMARY FUNDING SOURCE - National Institute of Allergy and Infectious Diseases.
To improve the efficacy of gemcitabine (GEM) for the treatment of advanced pancreatic cancer via local hyperthermia potentiated via a multi-functional nanoplatform permitting both in vivo heating and drug delivery is the goal of this study. Here, a chemohyperthermia approach to synergistically achieve high intra-tumoral drug concentrations, while permitting concurrent hyperthermia for more effective tumor cell kill and growth inhibition, is proposed. Drug delivery and hyperthermia are achieved using a hydroxypropyl cellulose (HPC)-grafted porous magnetic drug carrier that is MRI visible to permit in vivo visualization of the biodistribution. These synthesized magnetic drug carriers produce strong T2 -weighted image contrast and permit efficient heating using low-magnetic-field intensities. The thermomechanical response of HPC permits triggered GEM release confirmed during in vitro drug release studies. During in vitro studies, pancreatic cancer cell growth is significantly inhibited (≈82% reduction) with chemohyperthermia compared to chemotherapy or hyperthermia alone. Using PANC-1 xenografts in nude mice, the delivery of injected GEM-loaded magnetic carriers (GEM-magnetic carriers) is visualized with both MRI and fluorescent imaging techniques. Chemohyperthermia with intra-tumoral injections of GEM-magnetic carriers (followed by heating) results in significant increases in apoptotic cell death compared to tumors treated with GEM-magnetic carriers injections alone. Chemohyperthermia with GEM-magnetic carriers offers the potential to significantly improve the therapeutic efficacy of GEM for the treatment of pancreatic cancer. In vivo delivery confirmation with non-invasive imaging techniques could permit patient-specific adjustments therapeutic regimens for improve longitudinal outcomes.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
OBJECTIVES - To estimate the incidence of and risk factors for modifications to first antiretroviral therapy (ART) regimen, treatment interruption and death.
METHODS - A total of 21 801 patients from 18 cohorts in Europe and North America starting ART on regimens including at least two nucleoside reverse transcriptase inhibitors and boosted protease inhibitor or non-nucleoside reverse transcriptase inhibitor during 2002-2009 were included. Incidence of modifications (change of drug class, substitution/addition within class, or switch to nonstandard regimen), interruption or death and associations with patient characteristics were estimated using competing-risks methods.
RESULTS - During median 28 months follow-up, 8786 (40.3%) patients modified first ART, 2346 (10.8%) interrupted and 427 (2.0%) died before changing regimen. Three-year cumulative percentages of modification, interruption and death were 47, 12 and 2%, respectively. After adjustment, rates of interruption were highest for IDUs and lowest for MSM, and higher for patients starting ART with CD4 cell count above 350 cells/μl than other patients. Compared to efavirenz, patients on lopinavir and other protease inhibitors had higher rates of modification and interruption, on atazanavir had lower rates of class change, and on nevirapine higher rates of interruption. Those on tenofovir/emtricitabine backbone had lowest rates of substitutions and switches to nonstandard regimen, and on abacavir/lamivudine lowest rates of interruption. Rates of substitution and switches to nonstandard regimen were lower in 2006-2009.
CONCLUSION - Rates of modification and interruption were high, particularly in the first year of ART. Decreased rates of substitutions or switches to nonstandard regimen in recent years may be linked to greater use of well tolerated once-daily drugs.
OPINION STATEMENT - Cancers of the biliary tree represent a rare group of diseases with a devastating impact on patients. Gallbladder cancer often is associated with cholelithiasis. Cholangiocarcinoma may arise in the setting of biliary inflammation, such as primary sclerosing cholangitis, but most commonly occurs in patients without a particular risk factor. Surgical removal of biliary cancer is essential for cure, but it is associated with a very high rate of recurrence and for many patients is not possible at the time of diagnosis. Although risk factors differ for each anatomic site, systemic treatment is generally similar. Various adjunctive therapies, such as radiation and embolization, have been investigated for biliary tract cancers with modest success and efforts are ongoing to understand how to optimize these tools. Retrospective series and pooled analysis suggest a benefit for adjuvant treatment following resection, but prospective data are limited. Ongoing and planned phase 3 trials should help to clarify the role of adjuvant chemotherapy and radiation. For advanced disease, chemotherapy improves quality of life and survival, and gemcitabine with cisplatin represents the standard of care. However, all patients ultimately progress on this therapy, so clinical trials of new and better agents are essential to expand the existing treatment options for patients.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide. Although many regimens have been used for PDAC treatment, the combination of the EGF receptor (EGFR) inhibitor erlotinib with gemcitabine has been the only molecular-targeted drug tested so far that has been superior to gemcitabine alone. The mechanism underlying this effective combinational regimen remains unknown. Here, we show that the combination is superior to gemcitabine alone in blocking progression and prolonging survival in a murine model of PDAC (Kras activation with Tgfbr2 knockout). We found that gemcitabine induced mitogen-activated protein kinase signaling, which was dramatically inhibited by erlotinib even in the Kras-activated PDAC cells in the mouse model. Mechanistic investigations suggested that gemcitabine induces EGFR ligand expression and ERBB2 activation by increasing heterodimer formation with EGFR, thereby maintaining high levels of ERBB2 protein in PDAC cells. Overall, our findings suggest a significant role of ERBB in PDAC treatment.
BACKGROUND - Capecitabine, an oral 5-fluorouracil (5-FU) prodrug, is widely used in the treatment of breast, colorectal, and gastric cancers. To guide the selection of patients with potentially the greatest benefit of experiencing antitumor efficacy, or, alternatively, of developing toxicities, identifying genomic predictors of capecitabine sensitivity could permit its more informed use.
METHODS - The objective of this study was to perform capecitabine sensitivity genome-wide association studies (GWAS) using 503 well genotyped human cell lines from individuals representing multiple different world populations. A meta-analysis that included all ethnic populations then enabled the identification of novel germline determinants (single nucleotide polymorphisms [SNPs]) of capecitabine susceptibility.
RESULTS - First, an intrapopulation GWAS of Caucasian individuals identified reference SNP 4702484 (rs4702484) (within adenylate cyclase 2 [ADCY2]) at a level reaching genome-wide significance (P = 5.2 × 10(-8) ). This SNP is located upstream of the 5 methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene, and it is known that the enzyme for MTRR is involved in the methionine-folate biosynthesis and metabolism pathway, which is the primary target of 5-FU-related compounds, although the authors were unable to identify a direct relation between rs4702484 and MTRR expression in a tested subset of cells. In the meta-analysis, 4 SNPs comprised the top hits, which, again, included rs4702484 and 3 additional SNPs (rs8101143, rs576523, and rs361433) that approached genome-wide significance (P values from 1.9 × 10(-7) to 8.8 × 10(-7) ). The meta-analysis also identified 1 missense variant (rs11722476; serine to asparagine) within switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin (SMARCAD1), a novel gene for association with capecitabine/5-FU susceptibility.
CONCLUSIONS - Toward the goal of individualizing cancer chemotherapy, the current study identified novel SNPs and genes associated with capecitabine sensitivity that are potentially informative and testable in any patient regardless of ethnicity.
Copyright © 2011 American Cancer Society.