Agents In Oncology Research Articles

51P Shortcomings of immuno oncology (IO) agents application into real-world practise due to financial constraints in a resource constrained setting

Indications of IO have been on the rise with growing data across different cancers ranging from metastatic to earlier stages. However, applicability of the same into real world practise is limited in lower middle income countries due to financial constraints. Data is lacking in this regard. We conducted an observational study at our center to see applicability of IO indications across different cancers. Consecutive patients between Jan 2018 and Feb 2020 who had an indication for IO usage were enrolled and their treatment regimens studied. Patients across different primary sites were included with approved IO regimen .Reasons for non usage of IO were studied. Between Jan 2018 and Feb 2020 ,374 patients were enrolled who were eligible for treatment with IO either as a single agent or as combination .The most common indication was metastatic NSCLC (22.4%),head & neck (17.1%),RCC (11.2%) ,bladder (10.1%), endometrium (9.6%) ,HCC (10.1%) ,Hodgkins lymphoma (4.2%),melanoma (3.7 %) stage 3 NSCLC (5.3%) and so on .Of 374 patients ,only 114 (30.4%) were finally treated with IO regimen .The most common reason for non usage was financial constraints (80.7%) which included exhaustion of insurance limit ,denial by insurance company (11.5%) and non availability of drug (7.6%) .Of the 114 patients who were treated ,26.3% had to withdraw the drug owing to financial toxicity while the disease was still responding with the median time to withdrawal being 6.4 months. Our study depicts a real-world picture of practical difficulties in treating with approved regimens with financial constraints leading to non usage/withdrawal of drug in nearly 65% patients. This issue needs to be addressed if more patients are to be benefitted from IO agents in the future in lower middle income countries like India.

Mgta-145 / Plerixafor-Mediated HSC Mobilization and Intravenous HDAd5/35++ Vector Injection into Mice Allows for Efficient In Vivo HSC Transduction and Stable Gene Marking in Peripheral Blood Cells of CD46-Transgenic and Thalassemia Mice

Background. In vivo hematopoietic stem cell (HSC) gene therapy represents a simpler approach to treating hemoglobinopathies without the need for myelosuppressive conditioning and autologous HSC transplantation. We developed a helper dependent adenovirus (HDAd5/35++)-based platform that enables efficient in vivo transduction of mobilized HSCs via CD46. Transduced HSCs can be positively selected by low-dose O6BG/BCNU-treatment to achieve ~90% marking rates in peripheral blood. Initial proof-of-concept in murine models as well as in rhesus macaques demonstrates high level of g-globin expression after gene addition by a Sleeping Beauty transposase. While the current mobilization regimen-4 days of G-CSF injection followed by an injection of AMD3100/plerixafor on day 5-mobilizes HSCs from the bone marrow to the periphery, several issues exist. Despite widespread use as a mobilization agent in oncology, G-CSF is contra-indicated in patients with sickle cell disease. Additionally, G-CSF results in unselective bone marrow cell mobilization, which leads to leukocytosis and elevated numbers of cytokine-producing cells in the periphery that come into contact with HDAd particles, leading to high cytokine levels. Mobilized (committed) bone marrow cells in the periphery also sequester HDAd thus reducing the effective dose for primitive HSCs. Further, the five-day treatment regimen and high costs associated with G-CSF + plerixafor justify the development of an alternative mobilization regimen. A single-day, G-CSF-free mobilization regimen that mobilizes a high proportion of HSCs may therefore be preferred for in vivo gene therapy. Results . Here we tested HSC mobilization by truncated MGTA-145, a CXCR2 agonist, and plerixafor in the context of in vivo HSC transduction. CD46-transgenic animals were mobilized with GCSF + plerixafor (5 days) or with MGTA-145 + plerixafor (same-day treatment) and then injected one hour later with an integrating HDAd5/35++ mgmt/GFP vector. MGTA-145 + plerixafor resulted in robust mobilization of HSCs, less leukocytosis and no significant elevation of cytokines, as observed with G-CSF + plerixafor. With both mobilization regimens, after in vivo selection with O6BG/BCNU, >90% of PBMCs expressed GFP and marking rates were stable long-term. Mice were sacrificed 12 weeks after in vivo transduction and bone marrow lineage-negative cells were harvested for transplantation into secondary recipients. Stable transgene expression (>90% at week 16 after transplantation) was observed with both mobilization regimen in secondary recipients and multilineage engraftment was observed with MGTA-145 + plerixafor in primary and secondary recipients. Importantly, the mobilization with MGTA-145 + plerixafor worked efficiently in a mouse disease model for thalassemia (Hbbth3/CD46+/+). In this model, after in vivo transduction with an integrating HDAd5/35++mgmt/gamma-globin vector and in vivo selection, over 95% of peripheral red blood cells (RBCs) expressed human gamma-globin. The gamma-globin protein level reached 36% over mouse beta-globin. Phenotypic analyses showed a complete correction reflected by normal RBC morphology and absence of blood reticulocytosis, extramedullary hemopoiesis and hemosiderin deposition in spleen and liver sections. In secondary recipients of Lin- cells (harvested at week 14 from in vivo transduced Hbbth3/CD46+/+ mice), gamma-globin marking in RBCs was stable at 99% (currently at week 11 after transplantation). This demonstrates that MGTA145 + plerixafor mobilizes long-term repopulating HSCs. Conclusions . These data demonstrate that the combination of MGTA-145 and plerixafor could serve as an efficient and potentially safer one-day mobilization regimen for in vivo HSC gene therapy in patients with hemoglobinopathies. Disclosures Goncalves: Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Davis:Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kiem:Rocket Pharma: Membership on an entity's Board of Directors or advisory committees; Umoja: Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy; Homology Medicines: Membership on an entity's Board of Directors or advisory committees; Vor Biopharma: Membership on an entity's Board of Directors or advisory committees; Enochian: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy. Lieber:Ensoma, Inc: Consultancy, Research Funding.

Establishment and characterization of NCC-GCTB1-C1: a novel patient-derived cancer cell line of giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a rare osteolytic bone tumor, accounting for approximately 5% of all primary bone tumors. GCTB is characterized by unique giant cells. It is also characterized by recurrent mutations in the histone tail of the histone variant H3.3, H3F3A, on chromosome 1, therapeutic implications of which have not been established yet. There are few effective standardized treatments for GCTB, and a novel therapy has long been required. Patient-derived cancer cells have facilitated the understanding of mechanisms underlying the etiology and progression of multiple cancers. Thus far, only 10 GCTB cell lines have been reported, and none of them are publicly available. The aim of this study was to develop an accessible patient-derived cell line of GCTB, which could be used as a screening tool for drug development. Here, we describe the establishment of a cell line, designated NCC-GCTB1-C1, from the primary tumor tissue of a male patient with GCTB on the right distal radius. NCC-GCTB1-C1 cells were maintained as a monolayer culture for over 23 passages for 7months. These cells exhibited continuous growth, as well as spheroid formation and invasive ability. Using an oncology agent screen, we tested the effect of anticancer drugs on the proliferation of NCC-GCTB1-C1 cells. The cells displayed a remarkable response to romidepsin and vincristine. Thus, we established a novel GCTB cell line, NCC-GCTB1-C1, which could be a useful tool for studying GCTB tumorigenesis and the efficacy of anticancer drugs.

Abstract LB-386: Novel multimodal precision immunotherapy by co-targeting the HER3 oncogenic signaling circuitry and PD-1 for head and neck squamous cell carcinoma

Abstract In prior studies, we have shown that persistent activation of the PI3K/mTOR signaling circuitry is the most frequently dysregulated signaling pathway in HNSCC (>80% of all HPV- and HPV+ cases), and that mTOR inhibitors (mTORi) exert potent antitumor activity in multiple experimental HNSCC model systems and in a recent Phase 2 clinical trial. In this regard, the overreliance on PI3K/mTOR signaling for tumor growth may in turn expose a cancer vulnerability that can be exploited therapeutically. However, the immunosuppressive effects of mTORi limit the potential benefits of their combination with new immune oncology (IO) agents. These include immune check point blockade with pembrolizumab and nivolumab (anti-PD-1), which have recently demonstrated anti-tumor activity in HNSCC, albeit only <20% of the patients show durable responses. There is urgent need to search for alternative approaches for HNSCC treatment. We conducted a kinome-wide siRNA screen to identify new therapeutic targets for HNSCC. This revealed that the ERBB3 gene, encoding HER3, is among the top 20 kinases whose knockdown (KD) decreases HNSCC cell proliferation. A counter screen analysis revealed that ERBB3 was the gene whose KD results in the highest reduction of mTOR pathway activation (indicated by pS6). Remarkably, HER3 KD specifically reduced activation of mTOR but not ERK in cells that do not harbor PIK3CA mutations, and immunoprecipitation of HER3 showed direct binding between HER3 and PI3K. Furthermore, a blocking antibody targeting HER3 (CDX-3379) potently inhibited the tumor growth of PIK3CA wild type but not PIK3CA mutant HNSCC cells. CDX-3379 also showed anti-tumor activity in 4MOSC1, our recently reported tobacco-associated syngeneic HNSCC model. Of importance, we found that HER3 is not expressed in immune cells, but CDX-3379 treatment led to a rapid increase in the accumulation of pro-immunogenic IL-2 and IL-7, concomitant with a reduction in multiple pro-tumorigenic and immune suppressive cytokines (e.g., IL-10, VEGF, G-CSF, GM-CSF, IL-6). This provided a rationale to combine HER3i with IO agents. Indeed, the combination of HER3 and PD-1 blockade elicited a remarkable beneficial effect, with an increase of tumor-infiltrating CD8+ T cells and ~70% of the mice exhibiting complete and durable (>6 months) responses and consequently a significant increase in overall survival. Overall, our findings suggest that persistent tyrosine phosphorylation of HER3 underlies aberrant PI3K/mTOR signaling in HNSCC harboring wild type PIK3CA, and that targeting HER3 may exert its anti-tumor effect by both reducing cancer-driving mTOR activity and reversing an immune evasive tumor microenvironment. These findings also support that co-targeting the HER3 signaling circuitry combined with PD-1 blockade may represent a novel multimodal precision therapeutic approach for HNSCC aimed at achieving durable responses and cancer remission. Citation Format: Zhiyong Wang, Yusuke Goto, Mara Gilardi, Michael Allevato, Victoria Wu, Robert Saddawi-konefka, Diego Alvarado, Alfredo Molinolo, J. Silvio Gutkind. Novel multimodal precision immunotherapy by co-targeting the HER3 oncogenic signaling circuitry and PD-1 for head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-386.

Abstract 6284: GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy

Abstract Locoregional recurrence (LRR) is the major cause of morbidity and mortality in patients with squamous cell carcinoma of the head and neck (HNSCC). For those patients that experience surgically unresectable LRR, median overall survival (OS) is less than one year. Approaches utilizing stereotactic ablative radiotherapy (SAbR) and immune oncology agents such as Nivolumab (α-PD-1 agonist) in the salvage setting have become alternatives to conventional chemoradiation therapy. Despite improvements in OS, rates of acute oral mucositis (OM) and late toxicities (skin fibrosis) remain a concern with SAbR, particularly in the context of re-irradiation. Here we present pre-clinical evidence that GC4419 (Galera Therapeutics), a highly selective superoxide dismutase mimetic that recently received FDA Breakthrough therapy status following a Phase II, randomized, placebo controlled trial for reducing the duration and incidence of severe OM in patients undergoing chemoradiation therapy for locally advanced HNSCC (NCT02508389) also enhances the anti-tumor radiation response of HNSCC tumors to irradiation. We demonstrate in pre-clinical animal models that GC4419 protects the normal mucosa of the mouse tongue from radiation exposure. Utilizing clonogenic survival assays, GC4419 demonstrates single agent anti-cancer activity at physiologically achievable concentrations, while also enhancing the response of HNSCC lines to irradiation. In tumor growth delay (TGD) experiments utilizing the syngeneic HNSCC tumor model, AT-84, when GC4419 is delivered 30-60 minutes pre-irradiation with biologically equivalent fractionation schedules of 17 Gy x 1 fxn, 10.24 Gy x 2 fxn, or 5 Gy x 5 fxn, an enhancement of the radiation response is achieved. In tumor cure rate (TCD50) studies, GC4419 enhanced radiation exposure with a DEF of 1.25. Furthermore, when GC4419 is combined with radiation and an α-PD-1 inhibitor, a further enhancement of the radiation response is observed, indicating that GC4419 compliments radiotherapy combined with immune oncology. We will also report the results of ongoing studies examining the potency of GC4419 in protecting normal murine mucosa in the setting of reirradiation relevant to SAbR as a salvage therapy. This potentiation of the anti-tumor response with GC4419 is more pronounced at doses exceeding the threshold to be considered for intensity modulated radiation therapy (IMRT). The accompanying pre-clinical data strongly suggest that GC4419 should be combined with radio-immune therapy to not only enhance local tumor control, but that the potential for normal tissue protection with SAbR also creates the opportunity for dose escalation and may further improvement in treatment outcome. Citation Format: Brock James Sishc, Elizabeth Polsdofer, Debabrata Saha, Michael Story. GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6284.

Medication‐related 30‐day rehospitalizations in palliative care patients

AbstractPurposePrior studies suggest that inpatient palliative care services can reduce rehospitalizations. However, medications commonly prescribed by palliative care providers (eg, opioids, benzodiazepines, and antipsychotics) have been independently associated with rehospitalizations. Little is known regarding the role of adverse drug reaction (ADR)‐related rehospitalizations within the palliative care population.ObjectiveTo determine the prevalence and explore predictors of ADR‐related 30‐day rehospitalizations in an inpatient palliative care population.MethodsA retrospective cohort study that included 284 palliative care patients who were readmitted within 30‐days of discharge from two academic hospitals in Western Pennsylvania. All unplanned rehospitalizations were assessed for medication causality via the Naranjo algorithm by at least two independent reviewers.ResultsThe mean (SD) age of the cohort was 61 (16) years and included 45% (n = 127) female and 81% Caucasians (n = 229). Of the 254 unplanned rehospitalizations, 11 (4%) were classified as doubtful ADRs, 224 (88%) were classified as possible ADRs, and 19 (7%) were defined as probable or definite ADR‐related. Tacrolimus was associated with three probable and one definite ADR‐related rehospitalization. Oncologic agents (eg, venetoclax, nivolumab, vincristine, and decitabine, carfilzomib; n = 5), anticoagulants (eg, rivaroxaban, apixaban, and warfarin; n = 4), antimicrobials (eg, cephalexin and vancomycin; n = 2), potassium chloride (n = 2), lorazepam (n = 1), and nicotine replacement (n = 1) were all associated with probable ADRs. Only the number of medication changes during the index admissions was observed as a statistically significant predictor of rehospitalizations in this population (P = .043).ConclusionsPalliative care patients often suffer from potential ADR‐related rehospitalizations and the number of medication changes during the index hospital admissions is associated with future potential ADRs. Clinical pharmacists should consider these findings when developing initiatives to reduce rehospitalizations in the inpatient palliative care patient population.

A refined cocktailing of pro-apoptotic nanoparticles boosts anti-tumor activity

A functional 29 amino acid-segment of the helix α5 from the human BAX protein has been engineered for production in recombinant bacteria as self-assembling, GFP-containing fluorescent nanoparticles, which are targeted to the tumoral marker CXCR4. These nanoparticles, of around 34 nm in diameter, show a moderate tumor biodistribution and limited antitumoral effect when systemically administered to mouse models of human CXCR4+ colorectal cancer (at 300 μg dose). However, if such BAX nanoparticles are co-administered in cocktail with equivalent nanoparticulate versions of BAK and PUMA proteins at the same total protein dose (300 μg), protein biodistribution and stability in tumor is largely improved, as determined by fluorescence profiles. This fact leads to a potent and faster destruction of tumor tissues when compared to individual pro-apoptotic factors. The analysis and interpretation of the boosted effect, from both the structural and functional sides, offers clues for the design of more efficient nanomedicines and theragnostic agents in oncology based on precise cocktails of human proteins. Statement of significanceSeveral human pro-apoptotic peptides (namely BAK, BAX and PUMA) have been engineered as self-assembling protein nanoparticles targeted to the tumoral marker CXCR4. The systemic administration of the same final amounts of those materials as single drugs, or as combinations of two or three of them, shows disparate intensities of antitumoral effects in a mouse model of human colorectal cancer, which are boosted in the triple combination on a non-additive basis. The superiority of the combined administration of pro-apoptotic agents, acting at different levels of the apoptotic cascade, opens a plethora of possibilities for the development of effective and selective cancer therapies based on the precise cocktailing of pro-apoptotic nanoparticulate agents.

Systemic immunobiological, immunosuppressant, and oncologic agents for the treatment of dermatologic diseases during the SARS-CoV-2 (COVID-19) pandemic emergency: A quick review for a quick consultation.

The precision medicine era has helped to better manage patients with immunological and oncological diseases, improving the quality of life of this class of patients. Regarding the management of these patients and positivity to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), currently, limited data are available and information is evolving. In this quick review, we have analyzed the mechanisms of action and related infective risk of drugs used for the treatment of immune‐mediated and oncologic skin conditions during the daily clinical practice. In general, immunosuppressant and antineoplastic agents for dermatologic treatments do not require suspension and do not require special measures, if not those commonly observed. In the case of a coronavirus disease (COVID‐19) patient with complications (such as pneumonia, respiratory failure), treatment suspension should always be considered after taking into account the general condition of the patient, the risk‐benefit ratio, and the pathophysiology of COVID‐19 infection. The COVID‐19 emergency pandemic does not imply undertreatment of existing skin conditions, which together with the SARS‐CoV‐2 infection may jeopardize the patient's life.

Terapia personalizada em oncologia, considerando a farmacogenética e os atuais antineoplásicos

Os humanos podem expressar respostas terapêuticas muito diferentes quando é administrado o mesmo fármaco. No entanto, as variações podem ser devido ao fenótipo, pois, as diferenças na sua idade, peso, género, estado de saúde e dieta são uns dos fatores importantes, mas o genótipo também vem a contribuir com o meio. Contudo a implementação dos testes farmacogenéticos na prática clínica tem sido lenta. Existem ainda muitas barreiras presentes que levam a sua subutilização. O objetivo do presente trabalho é apresentar uma revisão sistemática em meta-analise sobre a terapia personalizada em oncologia, considerando a farmacogenética e os atuais antineoplásicos e como objetivos específicos: discutir sobre o desenvolvimento de farmacogenómica em relação aos antineoplásicos. De acordo com as estratégias de busca foram encontradas um total de 168 artigos nas bases de dados selecionadas para a busca, sendo 32 artigos na base de dados Pubmed, 24 na base de dados Lilacs e 12 na base de dados Scielo. Concluímos que o relacionamento à farmacocinética e dinâmica de medicamentos utilizados no tratamento de diferentes doenças, possa estar disponível em um grande banco de dados. Os benefícios da farmacogenética vão desde a escolha do fármaco que apresenta melhores efeitos terapêuticos até ao aumento da eficácia dos ensaios clínicos na descoberta de novos fármacos.

ASH highlights 2019: “aggressive B-cell lymphoma”

SummaryDespite its significant cure rate, diffuse large B‑cell lymphoma (DLBCL) remains a tumor entity of unmet medical need. The 2019 meeting of the American Society of Hematology (ASH) in Orlando, Florida, presented numerous directions, whereby clinicians may expect practice-changing innovations soon or in the near future. In this ASH highlight feature on “aggressive B‑cell lymphoma”, a selection of prominent findings will be summarized. Targeted therapeutics try to meet the needs of patients subgroups that would benefit, and novel immune oncology agents now represent established treatment principles for relapsed/refractory (R/R) DLBCL. Moreover, intense research efforts have been undertaken to identify biomarkers of response. Imaging-based and molecular diagnostic tools are becoming increasingly instrumental in appraising individual risk prior to the first treatment encounter and in the early phase of induction therapy. Genomic analyses of circulating tumor DNA conducted in the peripheral blood has gained attention in terms of assigning patients to dedicated tumor subtypes, monitoring their molecular tumor burden in the course of the disease, and steering personalized treatment extensions in the near future.

Acute interstitial nephritis with immunotherapy; a growing entity?

We report a case of acute kidney injury (AKI) secondary to immune-mediated acute interstitial nephritis (AIN), with supporting diagnostic results and a successful response to treatment. This entity is gaining increasing recognition with the burgeoning use of immunotherapy agents in oncology. The timeline for the development of AIN from the initiation of immunotherapy varies, and may range in severity from asymptomatic to severe, organ-threatening and with life threatening consequences. Renal biopsy should be performed to confirm the diagnosis due to the potential impact of discontinuation of immunotherapy on cancer survival. Re-challenge with immunotherapy is reasonable once renal function recovers.

PCN267 A MULTINATIONAL COMPARISON OF HTA DECISIONS FOR NEW TREATMENT OPTIONS IN ONCOLOGY IN 2019

New oncology agents are continuously scrutinised as payers consider innovative medicines with premium pricing. A retrospective analysis was performed on health technology assessments (HTA) between 2017 and 2019 by NICE (England), PBAC (Australia), and CADTH (Canada). An analysis was performed on oncology treatments approved by the European Medicines Agency. The assessment of these therapies by NICE, PBAC, and CADTH were reviewed and results analysed. An oncology HTA database containing published clinical and economic data from over 1200 HTA decisions was used. NICE published guidance from 28 oncology treatments in 2019. Positive recommendations were made in 92% of appraisals, compared to 86% in 2018 and 94% in 2017. In 2019, the same number of technologies were reimbursed via the cancer drugs fund (CDF) as were approved outright with a PAS. The ICER was an important element in decision-making. Where the accepted base-case ICER was under £50,000 per QALY gained, 100% of appraisals received a positive recommendation. 67% of those with base-case ICERs between £30,000 and £50,0000 were reimbursed through the CDF. In six HTAs, the committee was unable to conclude on the ICER and 83% of these were reimbursed through the CDF. CADTH conditionally recommended 75% of 32 new oncology treatments in 2019, mostly based on cost-effectiveness being improved to an acceptable level, a reduction compared to 95% in 2018 and 77% in 2017 (a further 12% were recommended unconditionally). PBAC published 20 HTAs in 2019, of which 40% were recommended, 15% deferred, and 45% rejected. This compares to 61% of treatments being recommended in 2018, and 42% in 2017. HTA decision-making varies by country. In England, 50% of positive HTAs were accepted by the CDF. whereas in Australia, treatments that were not recommended were deferred or rejected. Analysis of the main drivers behind decision-making will assist in understanding country differences.

Attempts to enhance the anti-cancer activity of curcumin as a magical oncological agent using transdermal delivery

For the past few years, curcumin has drawn the attention of scientists in multidisciplinary fields related to oncology and therapeutics. However, despite its high potency, its delivery suffers from several limitations and challenges that hinders the complete benefit from this magical molecule. Accordingly, this review demonstrates the several attempts and endeavors that the scientists exerted in order to delivery this molecule successfully through the transdermal route. We believe that the transdermal route of delivery of drugs can pose a new platform of targeting solid tumors such as the breast carcinoma so that applying a transdermal patch over the skin or the membrane covering the solid tumor can provide a means of the cure.

Tubulin Resists Degradation by Cereblon-Recruiting PROTACs.

Dysregulation of microtubules and tubulin homeostasis has been linked to developmental disorders, neurodegenerative diseases, and cancer. In general, both microtubule-stabilizing and destabilizing agents have been powerful tools for studies of microtubule cytoskeleton and as clinical agents in oncology. However, many cancers develop resistance to these agents, limiting their utility. We sought to address this by developing a different kind of agent: tubulin-targeted small molecule degraders. Degraders (also known as proteolysis-targeting chimeras (PROTACs)) are compounds that recruit endogenous E3 ligases to a target of interest, resulting in the target’s degradation. We developed and examined several series of α- and β-tubulin degraders, based on microtubule-destabilizing agents. Our results indicate, that although previously reported covalent tubulin binders led to tubulin degradation, in our hands, cereblon-recruiting PROTACs were not efficient. In summary, while we consider tubulin degraders to be valuable tools for studying the biology of tubulin homeostasis, it remains to be seen whether the PROTAC strategy can be applied to this target of high clinical relevance.

Impact of Pharmacy Benefit Managers on Oncology Practices and Patients.

Pharmacy benefit managers (PBMs) are thoroughly integrated into the drug supply chain as administrators of prescription drug benefits for private insurers, self-insuring business, and government health plans. As the role of PBMs has expanded, their opaque business practices and impact on drug prices have come under increasing scrutiny. PBMs are particularly influential in oncology care because prescription drugs play a major role in the treatment of most cancers and an increasing number of patients with cancer are treated with oral oncology agents managed by PBMs. There is concern that some PBM practices may threaten access to high-quality cancer care and may increase the financial and administrative burden on patients and practices. In this article, we review the role of PBMs in prescription drug coverage and reimbursement, discuss the impact of PBMs on oncology care, and present data from the 2018 ASCO Practice Survey assessing the knowledge and attitude of oncology practices toward PBMs.

Sevoflurane inhibits the proliferation and invasion of hepatocellular carcinoma cells through regulating the PTEN/Akt/GSK‑3β/β‑catenin signaling pathway by downregulating miR‑25‑3p.

Sevoflurane (Sevo) is one of the most frequently used volatile anesthetic agents in surgical oncology and has various effects on tumors, including inhibiting tumor growth, recurrence, and metastases; however, the molecular mechanisms are unknown. This study tried to investigate the influence of Sevo on hepatocellular carcinoma (HCC) cells and its possible mechanisms of action. The present study found that Sevo suppressed both the proliferative and invasive capabilities of both HCCLM3 and Huh7 cells in a dose-dependent manner. Moreover, 53 differentially expressed microRNAs (miRNAs/miRs) in HCC cells that resulted from Sevo were screened out using miRNA microarray assay. In particular, miR-25-3p displayed a significant decrease in response to Sevo treatment. Further studies showed that Sevo's inhibitory actions on HCC cells were attenuated by overexpression of miR-25-3p but enhanced by its inhibitor. Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN), a tumor suppressor gene, was directly targeted by miR-25-3p and its expression was upregulated by Sevo. In addition, Sevo suppressed the expression of phosphorylated-protein kinase B (p-Akt) (S473), glycogen synthase kinase (GSK) 3β (p-GSK3β) (S9), β-catenin, c-Myc and matrix metalloproteinase 9; whereas these inhibitory effects were reversed by miR-25-3p overexpression. More importantly, Sevo's tumor-suppressive effects were enhanced by LY294002 (a PI3-kinase inhibitor) but weakened by insulin growth factor-1 (an agonist of the Akt signaling pathway). These data suggest that Sevo's antitumor effects on HCC could be explained, in part, by Sevo inhibiting the miR-25-3p/PTEN/Akt/GSK-3β/β-catenin signaling pathway.

Trends in the delivery of care to oncology patients in the United States: Emphasis on the role pharmacists on the healthcare team.

The purpose of this study was to identify trends in oncology care that allow one to forecast workforce supply and demand, the training and skills needed by the oncology pharmacist for the likely future of oncology care. Interviews were conducted with experienced oncology pharmacists in leadership roles at 20 organizations balanced by geographic region and type of practice site (academic or community/ambulatory). Results were analyzed using descriptive statistics and theme identification. Practice sites differed widely in numbers of patient visits, practitioner/patient ratios, residency program presence, and other structural features. Despite this, the majority reported an expectation of growth in cancer patients, oncology physicians, oncology pharmacists, pharmacy technicians, oncology nurses, and advanced practice practitioners in the next two to five years. Fifty percent of sites currently support Post Graduate Year 2 (PGY2) oncology residencies. At least 50% reported routine pharmacist involvement in 12 clinical functions. More future involvement was predicted for immunotherapy (80%) and oral oncolytic therapy (90%). Interprofessional involvement was reported for a broad variety of practice-related committees and patient education teams. Limited pharmacist involvement in credentialing, quality measurement, and value-based reimbursement systems was found. Anticipated increases in demand for oncology pharmacists strongly suggest the need for more PGY2 oncology residency programs and on-the-job oncology training programs. Oncology pharmacists are currently involved in many clinical and administrative functions including multidisciplinary management. While a core set of clinical functions has been identified, oncology pharmacists must prepare for the increased use of oral oncology agents and immunotherapy. Pharmacist involvement in value-based reimbursement and other data-based quality outcome measurements should be increased to optimize involvement in team-based patient care.

Comparison of eight screening tools to detect interactions between herbal supplements and oncology agents

Patients with cancer are increasingly using herbal supplements, unaware that supplements can interact with oncology treatment. Herb-drug interaction management is critical to ensure optimal treatment outcomes. Several screening tools exist to detect drug-drug interactions, but their performance to detect herb-drug interactions is not known. This study compared the performance of eight drug-drug interaction screening tools to detect herb-drug interaction with anti-cancer agents. The herb-drug interaction detection performance of four subscription (Micromedex, Lexicomp, PEPID, Facts & Comparisons) and free (Drugs.com, Medscape, WebMD, RxList) drug-drug interaction tools was assessed. Clinical relevance of each herb-drug interaction was determined using Natural Medicine and each drug-drug interaction tool. Descriptive statistics were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value. Linear regression was used to compare performance between subscription and free tools. All tools had poor sensitivity (<0.20) for detecting herb-drug interaction. Lexicomp had the highest positive predictive value (0.98) and best overall performance score (0.54), while Medscape was the best performing free tool (0.52). The worst subscription tools were as good as or better than the best free tools, and as a group subscription tools outperformed free tools on all metrics. Using an average subscription tool would detect one additional herb-drug interaction for every 10 herb-drug interactions screened by a free tool. Lexicomp is the best available tool for screening herb-drug interaction, and Medscape is the best free alternative; however, the sensitivity and performance for detecting herb-drug interaction was far lower than for drug-drug interactions, and overall quite poor. Further research is needed to improve herb-drug interaction screening performance.

Outpatient dermatology consultations for oncology patients with acute dermatologic adverse events impact anticancer therapy interruption: a retrospective study.

Dermatologic adverse events (dAEs) of anticancer therapies may negatively impact dosing and quality of life. While therapy interruption patterns due to dAEs have been studied in hospitalized cancer patients, similar outcomes in outpatient oncodermatology are lacking. To analyse the therapy interruption patterns, clinico-histopathologic characteristics and management outcomes of outpatient dermatology consultations for acute dAEs attributed to the most frequently interrupted class of oncologic agents. We performed a retrospective cohort study of all cancer patients who received a same-day outpatient dermatology consultation for acute dAEs at our institution from 1 January to 30 June 2015. Relevant data were abstracted from electronic medical records, including demographics, oncologic history and explicit recommendations by both the referring clinician and consulting dermatologist on anticancer therapy interruption. Consultations with the most frequently interrupted class of oncologic treatment were characterized according to clinico-histopathologic features, dermatologic management and clinical outcomes. There were 426 same-day outpatient dermatology consultations (median age 59, 60% female, 30% breast cancer), of which 295 (69%) had systemic anticancer therapy administered within 30days prior. There was weak inter-rater agreement between referring clinicians and consulting dermatologists on interruption of anticancer treatment (n=150, κ=0.096; 95% CI -0.02 to 0.21). Seventy-three (25%) consultations involved interruption by the referring clinician, most commonly targeted therapy (24, 33%). Maculopapular rash was commonly observed in 23 consultations with 25 dAEs attributed to targeted agents (48%), and topical corticosteroids were most frequently utilized for management (22, 38%). The majority (83%) of consultations with targeted therapy-induced dAEs responded to dermatologic treatment and 84% resumed oncologic therapy, although three (19%) at a reduced dose. Rash recurred only in two instances (13%). A high frequency of positive outcomes in the management of targeted therapy-induced dAEs by outpatient consulting dermatologists and low recurrence of skin toxicity suggests impactful reductions in interruption of anticancer therapy.

Element discrimination via spectroscopic X-ray imaging with a CdTe Medipix3RX detector

X-ray imaging techniques that distinguish radiation in different energy ranges offer the advantage of material differentiation based on the material-specific properties of the object to be examined. One possibility to obtain spectroscopic information is the K-edge approach utilizing energy thresholds. A basic information about the photon energy is needed for this purpose. The Medipix3RX is a photon-counting semiconductor detector which provides multiple energy thresholds in a single recording and so an energy information. It offers up to eight independent energy thresholds per pixel with high spatial and high energy resolution. In order to investigate the possibility of material discrimination by X-ray imaging methods with Medipix3RX detectors, an absorption phantom was fabricated and examined which consists of 8 different materials in various thicknesses. For material separation the K-edge method was used, which exploits the abrupt rise of photo absorption for energies above the ionization energy of electrons in the atomic K-shell. After performing a threshold equalization and a threshold-energy calibration of the detector, X-ray images were taken of the phantom. After evaluation, five of the eight materials of the phantom were successfully separated and identified with the selected settings of the X-ray tube. These include gadolinium and iodine, which are used as contrast agents in oncology. The most reliable material discrimination was achieved for tungsten and gadolinium. Due to their high K-edge energy, they had the greatest influence on the spectrum used. Elements with a low atomic number, however, could be distinguished less confidently due to the low photo absorption in the energy spectrum used and the resulting low effect on the change of the measured total intensity. This article describes the experimental setup of the energy calibration and X-ray image analysis of a Medipix3RX detector with a 1 mm CdTe sensor as well as the performance and evaluation of these and shows first results in material identification with eight energy thresholds in spectroscopic single pixel mode configuration.