Samuel M.,Beatson Institute for Cancer Research |
Samuel M.,Center for Cancer Biology |
Lopez J.,University of California at San Francisco |
McGhee E.,Beatson Institute for Cancer Research |
And 13 more authors.
Cancer Cell | Year: 2011
Tumors and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen β-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters. © 2011 Elsevier Inc.
Wilmot V.V.,NHS Lothian |
Nixon I.J.,University of Edinburgh |
Nixon I.F.,Edinburgh Cancer Research Center
BMJ Case Reports | Year: 2016
Juvenile laryngeal papillomatosis is the commonest cause of benign epithelial tumours of the larynx. Following diagnostic biopsy, surgical debulking is the mainstay of therapy. The condition is often recurrent with further papillomas forming after debridement, requiring serial procedures and occasionally demanding tracheostomy. Rarely, the disease can undergo malignant transformation; most commonly to squamous cell carcinoma. We describe the first reported case of small cell neuroendocrine carcinoma occurring in the previous tracheostomy site of a 29-year-old male with a history of juvenile laryngeal papillomatosis. The patient, with a background of multiple treatments for juvenile papillomas, presented with voice change, breathing difficultly and erythema at the site of previous tracheostomy. Induction chemotherapy followed by chemoradiation was used to treat the lesion with a good response to initial therapy. © 2016 BMJ Publishing Group Ltd.
PubMed | NHS Lothian, University of Edinburgh and Edinburgh Cancer Research Center
Type: | Journal: BMJ case reports | Year: 2016
Juvenile laryngeal papillomatosis is the commonest cause of benign epithelial tumours of the larynx. Following diagnostic biopsy, surgical debulking is the mainstay of therapy. The condition is often recurrent with further papillomas forming after debridement, requiring serial procedures and occasionally demanding tracheostomy. Rarely, the disease can undergo malignant transformation; most commonly to squamous cell carcinoma. We describe the first reported case of small cell neuroendocrine carcinoma occurring in the previous tracheostomy site of a 29-year-old male with a history of juvenile laryngeal papillomatosis. The patient, with a background of multiple treatments for juvenile papillomas, presented with voice change, breathing difficultly and erythema at the site of previous tracheostomy. Induction chemotherapy followed by chemoradiation was used to treat the lesion with a good response to initial therapy.
PubMed | Medical Center Haaglanden, Catholic University of Korea, University of Alabama at Birmingham, Dana-Farber Cancer Institute and 14 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017
LBA2009 Background: Cilengitide (CIL) is a selective v3 and v5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8).This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients ( 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RTTMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RTTMZ alone. CIL was to be administered for 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety.272 patients received CIL plus TMZ/RTTMZ, and 273 were treated with TMZ/RTTMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS 1, respectively. 75% of patients of both arms were 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed.CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed.NCT00689221.
Garrett C.R.,University of Houston |
Bekaii-Saab T.S.,Ohio State University |
Ryan T.,New York University |
Fisher G.A.,Stanford University |
And 5 more authors.
Cancer | Year: 2013
BACKGROUND Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN-38 (10-hydroxy-7-ethyl-camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN-38 (EZN-2208) increases the solubility, exposure, and half-life of SN-38. Preclinical studies demonstrated superior in vitro efficacy of EZN-2208 when it was tested in irinotecan-refractory human CRC cell lines. METHODS Patients with metastatic or locally recurrent CRC who had previously received 5-flurouracil (5-FU), oxaliplatin, and irinotecan were assigned to receive EZN-2208 monotherapy (9 mg/m2 on days 1, 8, and 15 every 28 days for patients with KRAS-mutant tumors only [arm A]), and patients with KRAS wild-type tumors were randomized (2:1) to receive either EZN-2208 plus cetuximab (400 mg/m2 loading dose on day 1 followed by 250 mg/m2 weekly starting on day 8 [arm B]) or irinotecan 125 mg/m2 on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C). RESULTS The overall response rate and progression-free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2-5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1-5.8 months), respectively, in arm C. EZN-2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2-11.2 months) and arm C (9.1 months; 95% CI, 6.0-13.0 months). CONCLUSIONS EZN-2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression-free survival were similar in the cetuximab plus irinotecan arm and the EZN-2208 arm.
Dangoor A.,Bristol Haematology and Oncology Center |
Lorigan P.,Christie Hospital |
Keilholz U.,Charite Hospital |
Schadendorf D.,German Cancer Research Center |
And 9 more authors.
Cancer Immunology, Immunotherapy | Year: 2010
Background: Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens. Methods: Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-γ ELISPOT assays. Safety and clinical responses were monitored. Results: Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions. Conclusions: DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation. © 2009 Springer-Verlag.
Lamb R.,University of Manchester |
Ablett M.P.,University of Manchester |
Spence K.,University of Manchester |
Landberg G.,University of Manchester |
And 2 more authors.
PLoS ONE | Year: 2013
Introduction: Wnt signalling has been implicated in stem cell regulation however its role in breast cancer stem cell regulation remains unclear. Methods: We used a panel of normal and breast cancer cell lines to assess Wnt pathway gene and protein expression, and for the investigation of Wnt signalling within stem cell-enriched populations, mRNA and protein expression was analysed after the selection of anoikis-resistant cells. Finally, cell lines and patient-derived samples were used to investigate Wnt pathway effects on stem cell activity in vitro. Results: Wnt pathway signalling increased in cancer compared to normal breast and in both cell lines and patient samples, expression of Wnt pathway genes correlated with estrogen receptor (ER) expression. Furthermore, specific Wnt pathway genes were predictive for recurrence within subtypes of breast cancer. Canonical Wnt pathway genes were increased in breast cancer stem cell-enriched populations in comparison to normal breast stem cell-enriched populations. Furthermore in cell lines, the ligand Wnt3a increased whilst the inhibitor DKK1 reduced mammosphere formation with the greatest inhibitory effects observed in ER+ve breast cancer cell lines. In patient-derived metastatic breast cancer samples, only ER-ve mammospheres were responsive to the ligand Wnt3a. However, the inhibitor DKK1 efficiently inhibited both ER+ve and ER-ve breast cancer but not normal mammosphere formation, suggesting that the Wnt pathway is aberrantly activated in breast cancer mammospheres. Conclusions: Collectively, these data highlight differential Wnt signalling in breast cancer subtypes and activity in patient-derived metastatic cancer stem-like cells indicating a potential for Wnt-targeted treatment in breast cancers. © 2013 Lamb et al.
Nicum S.,University of Oxford |
Nicum S.,Churchill Hospital |
Roberts C.,University of Oxford |
Boyle L.,University of Oxford |
And 8 more authors.
BMC Cancer | Year: 2014
Background: BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumour cells with these mutations demonstrate increased sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin. Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. Methods: This multi-centre phase II single arm trial was designed to investigate the activity and safety of 6-mercaptopurine (6MP) 55 mg/m2 per day, and methotrexate 15 mg/m2 per week in patients with advanced breast or ovarian cancer, ECOG PS 0-2, progressing after ≥ one prior regimen and known to bear a BRCA1/2 germ line mutation. Accrual was planned in two stages, with treatment continuing until progression or unacceptable toxicity; in the first, if less than 3/30 evaluable patients respond at 8 weeks after commencing treatment, the trial will be stopped for futility; if not, then accrual would proceed to a second stage, in which if more than 9/65 evaluable patients are found to respond at 8 weeks, the treatment will be regarded as potentially effective and a phase III trial considered subject to satisfactory safety and tolerability. The primary outcome is objective response at 8 weeks, defined by RECISTS v1.1 as complete response, partial response or stable disease. Secondary outcomes include safety, progression- free and overall survival, and quality of life. Discussion: This study aims to investigate whether 6MP might be an effective treatment for BRCA deficient tumours even after the development of resistance to PARP inhibitors or platinum drugs. The study has surpassed the first stage analysis criteria of more than 3 out of 30 evaluable patients responding at 8 weeks, and is currently in the second stage of recruitment. Trial registration: NCT01432145 http://www. ClinicalTrials.gov. © 2014 Nicum et al.
Bartlett J.M.,Edinburgh Cancer Research Center
BMC cancer | Year: 2014
BACKGROUND: Taxanes such as paclitaxel and docetaxel are used successfully to treat breast cancer, usually in combination with other agents. They interfere with microtubules causing cell cycle arrest; however, the mechanisms underlying the clinical effects of taxanes are yet to be fully elucidated.METHODS: Isogenic paclitaxel resistant (PACR) MDA‒MB‒231, paclitaxel resistant ZR75‒1 and docetaxel resistant (DOCR) ZR75‒1 cell lines were generated by incrementally increasing taxane dose in native cell lines in vitro. We used aCGH analysis to identify mechanisms driving taxane resistance.RESULTS: Taxane resistant cell lines exhibited an 18-170 fold increased resistance to taxanes, with the ZR75-1 resistant cell lines also demonstrating cross resistance to anthracyclines. Paclitaxel treatment of native cells resulted in a G2/M block and a decrease in the G1 phase of the cell cycle. However, in the resistant cell lines, minimal changes were present. Functional network analysis revealed that the mitotic prometaphase was lost in the resistant cell lines.CONCLUSION: This study established a model system for examining taxane resistance and demonstrated that both MDR and mitosis represent common mechanism of taxane resistance.
PubMed | Dana-Farber Cancer Institute, Indiana University, Stanford University, University of Bern and 3 more.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016
Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline.We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE.When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials. Clin Cancer Res; 1-9. 2016 AACR.