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Dive into the research topics where Samuel Williams is active.

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Featured researches published by Samuel Williams.


Science Translational Medicine | 2017

A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions

Marc Damelin; Alexander John Bankovich; Jeffrey Bernstein; Justin Lucas; Liang Chen; Samuel Williams; Albert H. Park; Jorge Aguilar; Elana Ernstoff; Manoj Charati; Russell Dushin; Monette Aujay; Christina R. Lee; Hanna Ramoth; Milly Milton; Johannes Hampl; Sasha Lazetic; Virginia Pulito; Edward Rosfjord; Yongliang Sun; Lindsay King; Frank Barletta; Alison Betts; Magali Guffroy; Hadi Falahatpisheh; Christopher J. O’Donnell; Robert A. Stull; Marybeth A. Pysz; Paul Anthony Escarpe; David R. Liu

PTK7 is a tumor-initiating cell antigen, which can be targeted with an antibody-drug conjugate to confer sustained tumor regressions. Initiating an antitumor attack Cancer is notorious for relapsing after treatment, making it difficult to eradicate from a patient’s body. Such relapses are driven by tumor-initiating cells, a type of stem cells that give rise to tumors. Damelin et al. determined that a protein called PTK7 is frequently present on tumor-initiating cells and developed an antibody-drug conjugate for targeting it. The authors demonstrated the effectiveness of this therapy in mouse models of several tumor types and confirmed that it reduces tumor-initiating cells and outperforms standard chemotherapy. The antibody-drug conjugate also had some unexpected benefits, reducing tumor angiogenesis and promoting antitumor immunity, all of which may contribute to its effectiveness. Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non–small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient–derived xenografts (PDXs). To deliver a potent anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline–based linker, and Aur0101, an auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of cancer patients.


European urology focus | 2018

Long-term Outcomes of Follow-up for Initially Localised Clear Cell Renal Cell Carcinoma: RECUR Database Analysis

Saeed Dabestani; Christian Beisland; Grant D. Stewart; K. Bensalah; Eirikur Gudmundsson; Thomas Lam; William Gietzmann; Paimaun Zakikhani; Lorenzo Marconi; Sergio Fernández-Pello; Serenella Monagas; Samuel Williams; Christian Torbrand; Thomas Powles; Erik van Werkhoven; Richard P. Meijer; Alessandro Volpe; Michael Staehler; Börje Ljungberg; Axel Bex

BACKGROUNDnOptimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols.nnnOBJECTIVEnTo analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes.nnnDESIGN, SETTING, AND PARTICIPANTSnNonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI).nnnINTERVENTIONnPrimarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnIncidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used.nnnRESULTS AND LIMITATIONnOf 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n=53), intermediate- (n=105), and high-risk (n=128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p=0.004). Median OS was longer in PC compared with that in PI patients (p<0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort.nnnCONCLUSIONSnLow-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score-dependent FU approach is suggested.nnnPATIENT SUMMARYnWe analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies.


European Urology | 2018

Intensive Imaging-based Follow-up of Surgically Treated Localised Renal Cell Carcinoma Does Not Improve Post-recurrence Survival: Results from a European Multicentre Database (RECUR)

Saeed Dabestani; Christian Beisland; Grant D. Stewart; K. Bensalah; Eirikur Gudmundsson; Thomas Lam; William Gietzmann; Paimaun Zakikhani; Lorenzo Marconi; Sergio Fernández-Pello; Serenella Monagas; Samuel Williams; Christian Torbrand; Thomas Powles; Erik van Werkhoven; Richard P. Meijer; Alessandro Volpe; Michael Staehler; Börje Ljungberg; Axel Bex

The optimal follow-up (FU) strategy for patients treated for localised renal cell carcinoma (RCC) remains unclear. Using the RECUR database, we studied imaging intensity utilised in contemporary FU to evaluate its association with outcome after detection of disease recurrence. Consecutive patients with nonmetastatic RCC (n=1612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Recurrence occurred in 336 patients. Cross-sectional (computed tomography, magnetic resonance imaging) and conventional (chest X-ray, ultrasound) methods were used in 47% and 53%, respectively. More intensive FU imaging (more than twofold) than recommended by the European Association of Urology (EAU) was not associated with improved overall survival (OS) after recurrence. Overall, per patient treated for recurrence remaining alive with no evidence of disease, the number of FU images needed was 542, and 697 for high-risk patients. The study results suggest that use of more imaging during FU than that recommended in the 2017 EAU guidelines is unlikely to improve OS after recurrence. Prospective studies are needed to design optimal FU strategies for the future. PATIENT SUMMARY: After curative treatment for localised kidney cancer, follow-up is necessary to detect any recurrence. This study illustrates that increasing the imaging frequency during follow-up, even to double the number of follow-up imaging procedures recommended by the European Association of Urology guidelines, does not translate into improved survival for those with recurrence.


Wellcome Open Research | 2017

Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo

Rs Dickinson; Fiona Murphy; Catherine Doherty; Samuel Williams; Ananda S Mirchandani; Joseph Willson; John S. Scotti; Gail M. Preston; Christopher J. Schofield; Moira K. B. Whyte; Sarah R. Walmsley

Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis. The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods: In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro. In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain. This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host-pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest.


Archive | 2017

Transplantation and Immunology

Samuel Williams; James Richards

Transplantation involves the transfer of cells, tissues or organs from the donor to the recipient and has revolutionised the management of patients with end-stage organ failure.


Archive | 2015

ANTI-DLL3 ANTIBODIES AND DRUG CONJUGATES FOR USE IN MELANOMA

Samuel Williams; Laura Saunders; Kathryn A. Loving


Journal of Clinical Oncology | 2018

Imaging modalities used for follow-up of localized renal cell carcinoma (RCC) and subsequent effect on overall survival after recurrence: RECUR-database analysis.

Christian Beisland; Saeed Dabestani; Grant D. Stewart; K. Bensalah; Eirikur Guðmundsson; Thomas Lam; William Gietzmann; Paimaun Zakikhani; Lorenzo Marconi; Sergio Fernández-Pello; Serenella Monagas; Samuel Williams; Christian Torbrand; Thomas Powles; Erik van Werkhoven; Richard P. Meijer; Alessandro Volpe; Michael Staehler; Börje Ljungberg; Axel Bex


Journal of Clinical Oncology | 2016

Metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs) as novel indications for rovalpituzumab tesirine: A delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC).

Stanford Peng; Laura R. Saunders; Sheila Bheddah; Samuel Williams; Rahul Aggarwal; Jill E. Shea; Eun Y. Lee; Jiaoti Huang; Allison Zemek; Teri A. Longacre; Douglas W. Ball; Courtney L. Scaife; Barry D. Nelkin; Lowell B. Anthony; Pamela L. Kunz; Eric J. Small; Scott J. Dylla


Archive | 2017

ANTICUERPOS ANTI-MFI2 Y MÉTODOS DE USO

Mandy Boontanrart; Holger Karsunky; Laura Saunders; Samuel Williams


Archive | 2017

NOVEL ANTI-MFI2 ANTIBODIES AND METHODS OF USE

Samuel Williams; Laura Saunders; Holger Karsunky; Mandy Boontanrart

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Thomas Lam

University of Aberdeen

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Thomas Powles

Queen Mary University of London

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Axel Bex

Netherlands Cancer Institute

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Laura Saunders

University of California

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