Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer.

In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated ( ATM ) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo , and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.

Why Liver Cancer Hits Home: Bridging Healthcare Disparities in the Asian American and Pacific Islander Community.

Asian Americans and Pacific Islanders have an increased risk of developing liver cancer and higher risk of death compared to non-Hispanic White individuals. The role of individual-level risk factors, social determinants of health, and barriers navigating health systems present unique challenges in obtaining liver cancer care for these patients. Additionally, the Asian American and Pacific Islander population is a heterogenous group originating from several different countries and speaking various languages, and they are often underrepresented in cancer clinical trial populations. This article describes the challenges faced by Asian American and Pacific Islander patients with liver cancer from the clinician, research, and patient advocacy perspectives and proposes targeted solutions to reduce healthcare disparities in this group.

Patient-Reported Outcomes From the Phase III HIMALAYA Study of Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma.

PURPOSE: In the phase III HIMALAYA study (ClinicalTrials.gov identifier: NCT03298451) in unresectable hepatocellular carcinoma (uHCC), the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen significantly improved overall survival versus sorafenib, and durvalumab monotherapy was noninferior to sorafenib. Patient-reported outcomes (PROs), a secondary outcome from HIMALAYA, are reported here. METHODS: Participants were randomly assigned to receive STRIDE, durvalumab, or sorafenib. PROs were assessed (preplanned secondary outcome) using the European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire and the 18-item HCC module. Time to deterioration (TTD), change from baseline and improvement rate in global health status/quality of life (GHS/QoL), functioning, and disease-related symptoms were analyzed. RESULTS: In total, 1,171 participants were randomly assigned to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389) and were evaluable for PRO assessments. Across treatment arms, compliance rates for PROs were >77% at baseline and >70% overall. Baseline scores were comparable across treatment arms. TTD in GHS/QoL, physical functioning, fatigue, appetite loss, and abdominal pain was numerically longer for both STRIDE and durvalumab versus sorafenib. Clinically meaningful deterioration in PROs was not observed in any treatment arm. However, TTD in nausea and abdominal swelling was numerically longer for STRIDE versus sorafenib, and the likelihood of clinically meaningful improvement in GHS/QoL, role, emotional and social functioning, and disease-related symptoms was greater with STRIDE and durvalumab versus sorafenib. PROs with STRIDE and durvalumab were generally similar. CONCLUSION: Compared with sorafenib, STRIDE and durvalumab were associated with clinically meaningful, patient-centered GHS/QoL, functioning, and symptom benefits in people with uHCC. These findings support the benefits of the STRIDE regimen compared with sorafenib for a diverse population reflective of the global uHCC population.

Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update.

PURPOSE: To update an evidence-based guideline to assist in clinical decision-making for patients with advanced hepatocellular carcinoma (HCC). METHODS: ASCO convened an Expert Panel to update the 2020 guideline on systemic therapy for HCC. The panel updated the systematic review to include randomized controlled trials (RCTs) published through October 2023 and updated recommendations. RESULTS: Ten new RCTs met the inclusion criteria and were added to the evidence base. RECOMMENDATIONS: Atezolizumab + bevacizumab (atezo + bev) or durvalumab + tremelimumab (durva + treme) may be offered first-line for patients with advanced HCC, Child-Pugh class A liver disease, and Eastern Cooperative Oncology Group performance status 0-1. Where there are contraindications to these therapies, sorafenib, lenvatinib, or durvalumab may be offered first-line. Following first-line treatment with atezo + bev, second-line therapy with a tyrosine kinase inhibitor (TKI), ramucirumab (for patients with alpha-fetoprotein [AFP] ≥400 ng/mL), durva + treme, or nivolumab + ipilimumab (nivo + ipi) may be recommended for appropriate candidates. Following first-line therapy with durva + treme, second-line therapy with a TKI is recommended. Following first-line treatment with sorafenib or lenvatinib, second-line therapy options include cabozantinib, regorafenib for patients who previously tolerated sorafenib, ramucirumab (AFP ≥400 ng/mL), nivo + ipi, or durvalumab; atezo + bev or durva + treme may be considered for patients who did not have access to these therapies in the first-line setting, and do not have contraindications. Pembrolizumab or nivolumab are also options for appropriate patients following sorafenib or lenvatinib. Third-line therapy may be considered in Child-Pugh class A patients with good PS, using one of the agents listed previously that has a nonidentical mechanism of action with previously received therapy. A cautious approach to systemic therapy is recommended for patients with Child-Pugh class B advanced HCC. Further guidance on choosing between options is included within the guideline.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Alterations in BRCA2 as Determinants of Therapy Response in Prostate Cancer.

Prostate cancer (PCa) is one of the leading causes of cancer diagnoses and cancer-related deaths in the United States. Mutations or deletions in the genes involved in the DNA damage response (DDR) are common in aggressive primary PCa (germline alterations) and further enriched in advanced therapy-resistant PCa (somatic alterations). Among the DDR genes, BRCA2 is the most commonly altered (~ 13%) in advanced therapy-resistant PCa. Patients with BRCA2-altered PCas are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis). Indeed, two PARPis-olaparib and rucaparib have recently gained U.S. Food & Drug Administration approval for the treatment of advanced PCas harboring a BRCA2 mutation. This review seeks to explore the role of BRCA2 in DNA damage repair, the pathogenesis and progression of BRCA2 mutant PCa, and the utility of radiation therapy, targeted therapies, and platinum-based chemotherapies for patients with BRCA2 alterations.

Consistency of reports of violence from northern Rakhine state in August 2017.

BACKGROUND: In August 2017, Myanmar's Armed Forces, the Tatmadaw, launched an orchestrated attack on hundreds of Rohingya-majority villages in northern Rakhine state. This study seeks to validate the consistency of previous reports of violence against the Rohingya people in the region carried out by the Tatmadaw, Border Guard Police, and Rakhine villagers in the late summer and early fall of 2017. METHODS: Internal validation data is from a three-armed study. Data analyzed in the external triangulation was sourced through a literature review of known, publicly available surveys and interviews. Both sets of data documented instances of violence against the Rohingya people in northern Rakhine state during the late summer and early fall of 2017. Consistency was evaluated across five indicators of violence: arson, presence of mass graves, reports of sexual violence and human injuries, as well as human fatalities, across 611 locales in northern Rakhine state. Further analysis was conducted to measure consistency of reports by locale and across locales by indicator. RESULTS: Overall, an internal validation of 94 hamlets found that 98% of these locales were consistent across at least four of the five indicators (80% + consistency). Arson and reports of human injuries were the most consistent indicators across locales (100% and 99% consistency, respectively) and sexual violence was the least consistent indicator, with 84% of participating locales exhibiting consistent reports of sexual violence between the qualitative and quantitative data. Similarly, an external validation of 57 locations found that 50 of the 57 locations (88%) were consistent across indicators. Arson was the most consistent across sources (96%), whereas source agreement across locations was the least consistent for reports of sexual violence (58%). CONCLUSION: The government of Myanmar has denied involvement in the 2017 attacks on Rohingya communities in northern Rakhine state and purports that reports of the violence and destruction are overstated. However, consistent reporting from multiple sources on the same locales clearly underscores the veracity of the evidence documented, both by investigative groups and as recounted by Rohingya survivors of violence. It is our hope that this cataloging and comparison of available data, along with this study's assessment of its consistency, will aid ongoing accountability efforts.

Seeking justice amidst chaos: methods to identify and document individuals implicated in crimes against the Rohingya in August 2017.

BACKGROUND: Documenting perpetrators of human rights violations enables effective prosecution and can help prevent future atrocities. Doing so calls for collecting reliable data using verifiable and transparent methodology. We present methods used to document crimes and identify alleged perpetrators implicated in the 2017 attacks against Rohingya civilians in Myanmar. The findings and lessons-learned have relevance to contemporary crises with widespread atrocities. METHODS: A mixed-methods assessment conducted from May to July 2018 included: (1) cross-sectional quantitative surveys among leaders of affected hamlets in northern Rakhine State, (2) qualitative interviews to record hamlet-level accounts, and (3) clinical evaluations of survivors of violence. Survey respondents who reported violence and destruction in each hamlet were asked to identify perpetrators of those acts, including known role or affiliation. The reported names were reviewed for clarity and divergent spellings, repeated references were aggregated, and the names and roles were analyzed and classified by location and affiliation. RESULTS: 143 individuals were implicated in atrocities committed across three Northern Rakhine townships. Each was independently identified by at least three separate survey respondents as directly committing violence or destruction in their hamlet of origin, or as witnessed while fleeing to Bangladesh. Two-thirds (69%) of identified perpetrators were reported by four or more participants and 47% by five or more. Some form of additional identifying information, was provided for 85% of names. The most common affiliations were: Myanmar army (n = 40), Border Guard Police (n = 32), Village Tract Administrators (n = 17), and extremists (n = 25). CONCLUSIONS: The methodology presented here yielded a unique record of individuals purported to have directly committed acts of violence and destruction in Rakhine State in August 2017, forming the most extensive record of individuals implicated in ground-level perpetration of those crimes. This methodology can play a key role in accountability mechanisms for the Rohingya, and in other settings in which perpetrators are many and documentation of their crimes is difficult. The use of survey methods and standardized data collection amongst affected populations to comprehensively characterize crimes committed and to identify individuals implicated in those crimes can serve as a key tool in documentation and an important component of accountability.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma.

Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.

Potential Impact of IMbrave150 Results in the Evolving Treatment Landscape of Advanced Hepatocellular Carcinoma: A Multidisciplinary Expert Opinion.

A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.

Qualitative evidence of crimes against humanity: the August 2017 attacks on the Rohingya in northern Rakhine State, Myanmar.

BACKGROUND: The Rohingya ethnic minority population in northern Rakhine state, Myanmar, have experienced some of the most protracted situations of persecution. Government-led clearance operations in August 2017 were one of many, but notably one of the most devastating, attacks on the population. The study aimed to conduct a multiphase mixed-methods assessment of the prevalence and contexts of violence and mortality across affected hamlets in northern Rakhine State during the August 2017 attacks. This publication describes qualitative accounts by Rohingya community leaders from affected hamlets, with a focus on the events and environment leading up to and surrounding the attacks. METHODS: Qualitative in-depth interviews were conducted with Rohingya community leaders representing 88 northern Rakhine state hamlets across three townships affected by the August 2017 attacks (Maungdaw, n = 34; Buthidaung, n = 42; Rathedaung, n = 12). Prior quantitative surveys conducted among representative hamlet leaders allowed for preliminary screening and identification of interview candidates: interviewees were then selected based on prior reports of 10 or more deaths among Rohingya hamlet community members, mass rape, and/or witness of mass graves in a hamlet or during displacement. Recorded interviews were transcribed, translated, and thematically coded. RESULTS: Rohingya leaders reported that community members were subjected to systematic civil oppression characterized by severe restrictions on travel, marriage, education, and legal rights, regular denial of citizenship rights, and unsubstantiated accusations of terrorist affiliations in the months prior to August 2017. During the attacks, Rohingya civilians (inclusive of women, men, children, and elderly) reportedly suffered severe, indiscriminate violence perpetrated by Myanmar security forces. Crimes against children and sexual violence were widespread. Bodies of missing civilians were discovered in mass graves and, in some cases, desecrated by armed groups. Myanmar Armed Forces (Tatmadaw), consisting of the Army, Navy, and Border Guard Police continued to pursue, assault, and obstruct civilians in flight to Bangladesh. CONCLUSIONS: Qualitative findings corroborate previously published evidence of widespread and systematic violence by the Myanmar security forces against the Rohingya. The accounts describe intentional oppression of Rohingya civilians leading up to the August 2017 attacks and coordinated and targeted persecution of Rohingya by state forces spanning geographic distances, and ultimately provide supporting evidence for investigations of crimes against humanity and acts of genocide.

Discovery of phenyl acetamides as potent and selective GPR119 agonists.

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.

Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes.

We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT.

Production of a human neutralizing monoclonal antibody and its crystal structure in complex with ectodomain 3 of the interleukin-13 receptor α1.

Gene deletion studies in mice have revealed critical roles for IL (interleukin)-4 and -13 in asthma development, with the latter controlling lung airways resistance and mucus secretion. We have now developed human neutralizing monoclonal antibodies against human IL-13Rα1 (IL-13 receptor α1) subunit that prevent activation of the receptor complex by both IL-4 and IL-13. We describe the crystal structures of the Fab fragment of antibody 10G5H6 alone and in complex with D3 (ectodomain 3) of IL-13Rα1. Although the structure showed significant domain swapping within a D3 dimer, we showed that Arg(230), Phe(233), Tyr(250), Gln(252) and Leu(293) in each D3 monomer and Ser(32), Asn(102) and Trp(103) in 10G5H6 Fab are the key interacting residues at the interface of the 10G5H6 Fab-D3 complex. One of the most striking contacts is the insertion of the ligand-contacting residue Leu(293) of D3 into a deep pocket on the surface of 10G5H6 Fab, and this appears to be a central determinant of the high binding affinity and neutralizing activity of the antibody.

Disubstituted pyrimidines as Lck inhibitors.

We have developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cellular IL2 release.

Characterization of the NOD/scid-[Tg]DR1 mouse expressing HLA-DRB1*01 transgene: a model of SCID-hu mouse for vaccine development.

OBJECTIVE: We previously showed enhanced engraftment of human T cells in the transgenic NonObese Diabetic/severe combined immunodeficient (NOD/scid)-DR1 mice, compared to NOD/scid mice. We now characterize their immunobiology, innate immunity, and intrahepatic neonatal engraftment of cord blood mononuclear cells (CBMNC), and test immune responses of these chimeric mice to an experimental cancer vaccine. METHODS: Fluorescence in situ hybridization analysis, blood biochemistry, hematology, and fluorescein-activated cell sorting analyses of cellular subsets were performed on NOD/scid-DR1 mice, in comparison to parental NOD/scid mice. Innate immunity and lifespan were examined. Histology of engrafted tissues and short-term intrahepatic engraftment of CBMNC were performed. Intracellular interferon-gamma (IFN-gamma) production was assessed in mice immunized with cancer vaccine. RESULTS: The DR1 transgene was located on chromosome 5 and no significant changes were observed in blood chemistry, peripheral blood counts, lymphoid subsets, natural killer cell and lipopolysaccharide response, and antigen presentation in the NOD/scid-DR1 mice, compared to NOD/scid mice. Interestingly, NOD/scid-DR1 mice had a significantly longer lifespan (approximately 14 months) than NOD/scid mice (approximately 8.5 months). Engraftment with human cord blood cells resulted in slight changes in the architecture/structure of spleens. No correlation was found between DR1 genotype of the donor CBMNC and extent of engraftment of human T cells. Enhanced engraftment of human cells was observed with intrahepatic injections of CBMNC in neonatal NOD/scid DR1 mice. Intracellular IFN-gamma was detected in human cells, when chimeric mice were immunized with a cancer vaccine. CONCLUSION: NOD/scid-DR1 mice were similar in most of the physiological parameters as the NOD/scid mice, with the exception of longer lifespan. Intrahepatic engraftment of neonatal mice is the preferred protocol of xenotransplantation in this model and the engrafted human cells can respond to a cancer vaccine.

A recombinant 63-kDa form of Bacillus anthracis protective antigen produced in the yeast Saccharomyces cerevisiae provides protection in rabbit and primate inhalational challenge models of anthrax infection.

Infection by Bacillus anthracis is preventable by prophylactic vaccination with several naturally derived and recombinant vaccine preparations. Existing data suggests that protection is mediated by antibodies directed against the protective antigen (PA) component of the anthrax toxin complex. PA is an 83-kDa protein cleaved in vivo to yield a biologically active 63-kDa protein. In an effort to evaluate the potential of yeast as an expression system for the production of recombinant PA, and to determine if the yeast-purified rPA63 can protect from a lethal inhalational challenge, the sequence of the 63-kDa form of PA was codon-optimized and expressed in the yeast Saccharomyces cerevisiae. Highly purified rPA63 isolated from Saccharomyces under denaturing conditions demonstrated reduced biological activity in a macrophage-killing assay compared to non-denatured rPA83 purified from Escherichia coli. Rabbits and non-human primates (NHP) immunized with rPA63 and later challenged with a lethal dose of B. anthracis spores were generally protected from infection. These results indicate that epitopes present in the 63-kDa from of PA can protect rabbits and non-human primates from a lethal spore challenge, and further suggest that a fully functional rPA63 is not required in order to provide these epitopes.

The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection.

A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.

Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9.

Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.

p38 Inhibitors: piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones.

We have synthesized a series of C7-piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones that are highly potent inhibitors of both p38MAP kinase activity and TNF-alpha release. The 4-aminopentamethylpiperidine naphthyridinone 5, which was designed to block metabolism at major 'hot spots', combined excellent inhibitory potency with good oral bioavailability in the rat.