tbuckley/cabot-search huggingface dataset:
Value for money in genitourinary oncology.
Authors: David Edward O Reilly, Ronan Andrew McLaughlin, Anne-Marie DeFrein, Cian Ronayne, Bojan Macanovic, David McMahon, Derek Gerard Power, Richard Martin Bambury, Dearbhaile Catherine Collins
Journal: Journal of Clinical Oncology (2021)

1 Background: Innovation in the treatment of genitourinary (GU) malignancies is accelerating, however, many of these new treatments are often not available for patients. We sought to investigate patient access, cost and value of new systemic anti-cancer compounds (SACTs) in GU oncology. We compared the US and Europe with a focus on the United Kingdom (UK) and the Republic of Ireland (IRL). Methods: Data on licensing and reimbursement decisions was collected on SACTs approved for GU oncology between 01/01/2010 to 09/01/2020. Overall survival (OS) benefit, progression free survival (PFS) benefit and cost of therapy were included in our analysis. Results: There were 29 regimens/indications approved by the Federal Drug Agency (FDA) for GU malignancies between 2010 and 2020. The majority of these (21/29, 72%) were also approved by the European Medicines Agency (EMA). Nearly all regimens/indications were approved by the FDA prior to the EMA (27/29, 93%), with a median time to EMA approval of 4 months (SD = 6, range -6 to 17). Only a minority of these regimens/indications are reimbursed by the public health systems in the UK (12/29, 41%) and IRL (6/29, 21%). Following EMA approval, public reimbursement of these regimens in the UK and IRL is often delayed with a median time of 8 months (+/- 6.3, range 4 - 21) and 11.5 months (+/- 12.5, range 0 - 33) respectively. Approximately half (15/29, 52%) of all reimbursed regimens/indications have demonstrated an overall survival benefit for patients. Androgen signalling inhibitors (ASIs) are more likely to have a proven OS benefit and had a lower mean cost than non-ASI regimens (See Table). A significant minority of regimens/indications (6/29, 21%) have demonstrated neither an OS or PFS benefit. The median price per month (USA list price) was $15,086 +/- $7,019. Regimens with a proven OS benefit were not more expensive than those without ($14,229 +/- $6,466 versus $16,004 +/- $7,704). There was no significant correlation between the length of OS benefit and the cost of regimens (Pearson’s Correlation Coefficient = -2.72, p = 0.445). Conclusions: Patients in the UK and IRL experience clinically significant delays in accessing FDA approved regimens in GU oncology. Only 52% of these regimens have a proven OS benefit. In our study, ASI regimens are cheaper and more effective than non-ASI regimens. There is no association between overall survival benefit and list prices in the USA. We need to radically overhaul licensing and funding of SACTs in GU oncology to ensure continued access for patients to effective medicines. [Table: see text]
Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy
Authors: Cristian Sandoval-Acuña, Natalia Torrealba, Veronika Tomkova, Sukanya B. Jadhav, Kristyna Blazkova, Ladislav Merta, Sandra Lettlova, Miroslava K. Adamcová, Daniel Rosel, Jan Brábek, Jiri Neuzil, Jan Stursa, Lukas Werner, Jaroslav Truksa
Journal: Cancer Research (2021)

Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (i) impairment of iron-sulfur [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (ii) inhibition of mitochondrial respiration leading to mitochondrial reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anticancer drug via mitochondrial targeting. SIGNIFICANCE: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2289/F1.large.jpg.
Regulation of OATP1B1 Function by Tyrosine Kinase–mediated Phosphorylation
Authors: Elizabeth R. Hayden, Mingqing Chen, Kyle Z. Pasquariello, Alice A. Gibson, James J. Petti, Shichen Shen, Jun Qu, Su Sien Ong, Taosheng Chen, Yan Jin, Muhammad Erfan Uddin, Kevin M. Huang, Aviv Paz, Alex Sparreboom, Shuiying Hu, Jason A. Sprowl
Journal: Clinical Cancer Research (2021)

Abstract Purpose: OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug–drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI). Experimental Design: OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured in vivo. Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS–based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases. Results: Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin in vivo, and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations. Conclusions: A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.
Impact of angiotensin blockade on response to PD1/L1 inhibitors for patients with metastatic urothelial carcinoma (mUC).
Authors: William Paul Skelton, Rohit K. Jain, Catherine Curran, Gregory Russell Pond, Syeda Mahrukh Hussnain Naqvi, Youngchul Kim, Pier Vitale Nuzzo, Sarah Abou Alaiwi, Amin Nassar, Rakesh K. Jain, Guru Sonpavde
Journal: Journal of Clinical Oncology (2021)

453 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis and cell proliferation. Preclinical data also indicate that angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients (pts) with metastatic urothelial carcinoma (mUC) receiving PD1/L1 inhibitors, we hypothesized that angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mUC pts receiving PD1/L1 inhibitors. Methods: Data from mUC pts who received PD1/L1 inhibitors as monotherapy were obtained: pts from the Dana-Farber Cancer Institute (DFCI) served as the discovery dataset, while data from Moffitt Cancer Center (MCC) served as the validation dataset. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting PD1/L1 inhibitor treatment. A logistic regression was used to investigate the impact of concurrent ACEI/ARB on any regression of tumor (ART, any decrease in size of tumor on scan) as the primary endpoint defined as any tumor regression after controlling for known prognostic factors (performance status, sites of metastasis, neutrophil/lymphocyte ratio, platelet count, hemoglobin). Overall survival (OS), the secondary endpoint, was analyzed using Cox proportional hazards regression. Results: Data was available for 178 pts from DFCI (discovery dataset) with mUC who received a PD1/L1 inhibitor of whom 153 (86%) had received prior platinum and 33 pts (18.5%) received concurrent AECI/ARBs. Multivariable analysis controlling for known prognostic factors revealed that patients who received ACEIs or ARBs had greater ART (HR 3.0 [95% CI 1.25-7.17], p = 0.014) and improved OS, (HR 0.49 [95% CI 0.28-0.88] p = 0.016). In the MCC validation dataset, 101 pts were available of whom 59 (58.4%) had received prior platinum and 22 pts (21.8%) received concurrent ACEI/ARBs. Univariate analysis showed that those patients who were treated with ACEI/ARB had an improved ART (OR 3.32 [95% CI 1.22-9.06] p = 0.019). On multivariable analysis, there was a borderline significant association of ACEI/ARB with ART (OR = 3.03, p = 0.075), but no association was observed with OS. Conclusions: In this hypothesis-generating study, concurrent angiotensin inhibitors including ACEI or ARBs were associated with tumor regression in mUC pts receiving PD-1/L1 inhibitors. The inconsistent association with OS may be partly due to modest sample size and comorbidities associated with the need for ACEI/ARBs. These results require validation in a prospective study.
Racial diversity and reporting in FDA registration trials for genitourinary (GU) cancers from 2006-20.
Authors: Mark Lythgoe, Maximilian Julve, Jonathan Krell, Philip Savage, Petros Grivas, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2021)

22 Background: GU cancers account for 1 in 5 of new cancer diagnoses in the USA. Significant racial disparities exist in terms of incidence, treatment and outcomes. Current FDA clinical trial guidance advises race reporting as a minimum of 5 categories (White/Caucasian, Black, Asian, American Indian or Alaskan Native [AIAN] and Native Hawaiian or Pacific Islander [NHPI]). Guidelines from the International Committee of Medical Journal Editors (ICMJE) recommend that authors should as a minimum, provide descriptive data for variables such as race and ethnicity. We analysed racial diversity in GU registration trials and compliance with FDA/ICMJE guidance in reporting. Methods: A retrospective review of new market authorisations in GU cancers from Jan 2006 to Oct 2020 was conducted utilizing the FDA website. Clinical trials cited on the licensing label for market authorization were recorded and corresponding registration trial publication identified. If race was unreported or partially reported (defined ≤3 groups), then the trial report on clinicaltrials.gov or FDA website was analysed. Total proportion of racial group participation and the proportion of registration trials with adequate reporting was determined. Results: We identified 42 new licensing indications, involving 33 unique drugs. Overall 30,316 patients participated in GU cancer registration trials; 21,068 (69.5%) White or Caucasian, 2516 (8.3%) Asian, 621(2%) Black or African American, 92 (0.3%) AIAN, 17 (0.1%) NHPI, 558 (1.8%) other or multiple races and 5463 (18%) unknown. Table shows breakdown by tumour group. Race reporting occurred in 23 (55%) registration trial publications, of which 5 provided only limited information (e.g. Caucasian only). For studies where no race information was reported, a further 10 (24%) had information within the trial report. In the 5 years prior to the introduction of FDA guidance in 2016 only 30% of registration studies met FDA/ICJME requirements. Since 2016 this has improved significantly to 60%. Conclusions: Despite the higher incidence of GU cancers in non-white populations, this study has revealed the relative over-representation of white participants in GU registration trials. The inclusion of black trial participants is in particular disproportionately low when compared to the burden of disease in this population group. Recruitment of black and other minority participants should be a research priority. [Table: see text]
Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection
Authors: Rania El Fekih, James Hurley, Vasisht Tadigotla, Areej Alghamdi, Anand Srivastava, Christine Coticchia, John Choi, Hazim Allos, Karim Yatim, Juliano Alhaddad, Siawosh Eskandari, Philip Chu, Albana B. Mihali, Isadora T. Lape, Mauricio P. Lima Filho, Bruno T. Aoyama, Anil Chandraker, Kassem Safa, James F. Markmann, Leonardo V. Riella, Richard N. Formica, Johan Skog, Jamil R. Azzi
Journal: Journal of the American Society of Nephrology (2021)

Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%.Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.
Response to: ‘Correspondence on ‘Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement’’ by Banday<i>et al</i>
Authors: Peter Nash, Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2021)

Response to: 'Correspondence on 'Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement'' by Banday et alWe thank Banday et al for their correspondence and their concise summary of information about monogenic interferonopathies and the response to various Jak inhibitors. 1 As we have detailed in the paper, the Jakinib consensus statement and the associated systematic literature research 2 3 focused on: 1. Practical information for the clinician to assist with Jakinib therapy once the decision is made to prescribe a Jakinib no matter which disease indication exists such as those discussed in the correspondence.2. Entailed strict criteria for study inclusion which in particular excluded small cohort studies such as those quoted in the correspondence, moreover.3. Off label indications for Jakinib use such as the monogenic interferonopathies were also excluded pending future high quality randomised clinical trials (RCTs) for peer-reviewed assessment of Jakinib therapy, although understandably this is difficult in orphan diseases that are rare and meaningful numbers to study the efficacy and safety of any therapy is a real challenge.With respect to the interferonopathies, we cited three publications, including both sting-associated vasculopathy infantile onset (SAVI) syndrome and USP18 disease which are regarded as interferonopathies as mentioned by Banday et alIn line with the conclusion in the correspondence that 'the data are still not plentitude', we look forward to future developments in this field and hope that these developments will lead to approval of Jakinibs for interferonopathies in the near future.
TERT promoter mutation as a prognostic marker in patients with advanced urothelial carcinoma treated with immune checkpoint inhibitors.
Authors: Ivan de Kouchkovsky, Li Zhang, Errol Philip, Francis Wright, Daniel Myung Kim, Divya Natesan, Daniel Kwon, Hansen Ho, Son Ho, Emily Chan, Sima P. Porten, Arpita Desai, Franklin W. Huang, Jonathan Chou, David Yoonsuk Oh, Raj Pruthi, Lawrence Fong, Eric Jay Small, Terence W. Friedlander, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2021)

476 Background: Reliable predictive markers are lacking in patients (pts) with locally advanced or metastatic urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICI). We sought to determine whether specific genomic alterations could be used to predict overall survival (OS) in this patient population. Methods: We undertook a retrospective cohort study of pts with aUC who received ICI and underwent genomic profiling by next-generation sequencing (NGS). All patients underwent NGS using commercially available platforms (e.g. Foundation Medicine, Strata, Invitae), or testing on the CLIA-certified institutional panel UCSF500. Associations between the 20 most frequently altered genes and OS were first examined by Cox regression. Genes with a p &lt;0.1 on univariate analysis and relevant clinical variables were then included in a multivariable analysis. Results: We identified 78 pts treated with ICI for aUC with available genomic profiling results. Median age at ICI initiation was 71; the majority of patients had visceral metastases (70.5%), ECOG performance status ≤1 (62.8%) and received ICI in the post-platinum setting (52.6%). Objective response rate in this cohort was 35.9%, median progression free survival was 4.0 months (95% CI 2.6-10.5) and median OS was 17.5 months (95% CI 14.1-NR) from ICI start. The most commonly altered genes were the TERT promoter (TERTp) (61%), TP53 (52%), RB1 (31%), CDKN2A(29%) and CDKN2B (27%). On univariable analysis there was a trend towards longer OS in pts with TERTp mutations (HR 0.53, 95% CI 0.27-1.06, p = 0.07), and shorter OS in pts with CDKN2B mutations (HR 1.91, 95% CI 0.98-3.73, p = 0.06). Both mutations were included in a multivariable analysis. After adjusting for known prognostic variables (ECOG PS, visceral metastases, albumin, hemoglobin, body mass index [BMI], neutrophil to lymphocyte ratio [NLR], and histology), the presence of a TERTp mutation was significantly associated with improved OS (HR 0.30, 95% CI 0.10-0.93, p = 0.04; Table). Conclusions: The presence of a TERTp mutation was an independent predictor of improved OS in a cohort of aUC pts treated with ICI. Other common mutations and clinical variables were not associated with OS on a multivariable analysis. These findings are hypothesis-generating and prospective validation is needed. [Table: see text]
A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with <i>de novo</i> metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281).
Authors: Karim Fizazi, Daniel J. George, Maria De Santis, Noel Clarke, Andre P. Fay, Hirotsugu Uemura, Lynda Grinsted, Claire Rooney, Remy B Verheijen, Rana Anjum, Andrew Foxley, Thomas Morris
Journal: Journal of Clinical Oncology (2021)

TPS178 Background: In metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone combined with androgen deprivation therapy (ADT) is highly effective in improving patient outcomes. However, around 20% of patients progress to castration-resistant disease within 12 months of treatment; these patients have shorter survival and limited treatment options. Aberrant activation of the PI3K/AKT pathway, predominately due to PTEN loss, is common in prostate cancer, especially in later-stage disease. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated such as that inhibition of one leads to upregulation of the other. Therefore, combining abiraterone therapy with AKT inhibition may be beneficial in patients with mHSPC who have PTEN deficiency. In preclinical studies, capivasertib, a selective oral pan-AKT inhibitor, inhibited proliferation of models of hormone-sensitive and castration-resistant prostate cancer with PTEN loss. The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. CAPItello-281 (NCT04493853) is a global, multicenter, phase 3 trial to evaluate capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. Methods: Eligible patients for this double-blind, randomized trial are men aged 18 years or older with confirmed newly diagnosed previously untreated metastatic hormone-sensitive prostate adenocarcinoma with immunohistochemically confirmed PTEN deficiency and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Following screening, approximately 1000 patients will be randomized 1:1 to receive either capivasertib (400 mg) or placebo (twice daily; 4 days on, 3 days off) in combination with abiraterone (1000 mg once daily) and ADT until radiographic progression or intolerable toxicity. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020. Acknowledgments: We thank Julia Grigorieva, PhD, of Oxford PharmaGenesis, Philadelphia, USA, for providing medical writing assistance. Funding: The CAPItello-281 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04493853.
33O A phase I study to evaluate safety, pharmacokinetics (PK), and preliminary efficacy of CYH33, a phosphatidylinositol 3-kinase α (PI3Kα) inhibitor, in patients (pts) with advanced solid tumours
Authors: X-L. Wei, J-H. Liu, H. Zhao, Y. Zhang, Q-W. Liu, B-Y. Zou, F. Wang, Z-Q. Wang, M-Z. Qiu, Q-Q. Yu, Y-W. Du, R-H. Xu
Journal: Annals of Oncology (2021)