Cell Context Is the Third Axis of Synergy for the Combination of ATR Inhibition and Cisplatin in Ewing Sarcoma.

PURPOSE: The importance of cellular context to the synergy of DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR-targeted combination therapy for Ewing sarcoma. EXPERIMENTAL DESIGN: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for Ewing sarcoma selectivity, and optimized for in vivo schedule. RESULTS: Berzosertib combined with cisplatin demonstrates profound synergy in multiple Ewing sarcoma cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell-cycle check-points, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of CHEK1 expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of Ewing sarcoma models, leading to durable complete responses in 50% of animals bearing two different Ewing sarcoma xenografts. CONCLUSIONS: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule. See related commentary by Ohmura and Grünewald, p. 3358.

Importance of pharmacologic considerations in the development of targeted anticancer agents for children.

PURPOSE OF REVIEW: The purpose of this review is to describe key pharmacologic considerations to inform strategies in drug development for pediatric cancer. RECENT FINDINGS: Main themes that will be discussed include considering patient specific factors, epigenetic/genetic tumor context, and drug schedule when optimizing protocols to treat pediatric cancers. SUMMARY: Considering these factors will allow us to more effectively translate novel targeted therapies to benefit pediatric patients.

Clinical outcomes of thyroid tumours with concurrent epithelial and mesenchymal components in 14 dogs (2006-2020).

BACKGROUND: While rare, multiple individual case reports have described mixed thyroid tumours in dogs containing both epithelial and mesenchymal neoplastic components. OBJECTIVES: In this retrospective case series, we describe the clinical presentation, treatment and outcome of 14 dogs of canine thyroid tumours with concurrent mesenchymal and epithelial neoplastic populations. METHODS: Fourteen cases were retrospectively abstracted from nine institutions. Histopathologic samples and reports were collected from 10/14 dogs and reviewed by a single board-certified anatomic pathologist. RESULTS: All 14 dogs had curative-intent surgery to remove the thyroid neoplasm. The most common surgery performed was a unilateral thyroidectomy (10/14 dogs). Postoperatively, systemic therapy was administered in eight dogs. Six dogs developed local recurrence with a median time to loco-regional recurrence of 53 days. Ten dogs developed metastatic disease with the most common metastatic site being the lungs (6/10 dogs), with a median time to metastasis of 93 days. Ten dogs were euthanised due to locoregional or distant progression of their mixed thyroid neoplasm. The overall median survival time was 156 days (95%CI: 49-244). The median survival time for dogs treated with adjuvant therapy was 189 days (95%CI: 24-244), whereas dogs without adjuvant therapy had a median survival time of 156 days (95%CI: 35-upper limit could not be calculated; p = 0.62). CONCLUSION: The thyroid tumours with both mesenchymal and epithelial components in this small sample set were associated with a poor prognosis after surgical excision with or without adjunctive therapy.

Canine leishmaniasis in Northern California-A case report.

A 3-year-old dog was referred to the Veterinary Medical Teaching Hospital of the University of California-Davis for further evaluation of episodes of epistaxis of 1-year duration and peripheral lymphadenopathy. The patient had a history of atopic dermatitis with no travel history outside of California. Hyperglobulinemia with a polyclonal gammopathy was noted on serum protein electrophoresis. Microscopic evaluation of a bone marrow aspirate sample revealed many free and intra-cellular amastigotes of Leishmania sp. that was further confirmed by qPCR as L infantum. This is, to the best of our knowledge, the first reported case of canine leishmaniasis in the state of California. The patient is believed to have been vertically infected from the dam who is from Serbia and remained subclinical until presentation. Because the clinical progression of leishmaniasis is variable, it is important that precautions be discussed with owners acquiring puppies with dams from endemic regions of leishmaniasis to prevent zoonotic exposure in states where competent vectors are present.

Efficacy and toxicity of mustargen, vincristine, procarbazine and prednisone (MOPP) for the treatment of relapsed or resistant lymphoma in cats.

OBJECTIVES: The aims of this study were to evaluate the safety of mustargen, vincristine, procarbazine and prednisone (MOPP) chemotherapy in the treatment of relapsed or refractory feline lymphoma, and to determine the overall response rate and median remission time with this protocol. METHODS: The medical records of 38 cats with relapsed or refractory lymphoma treated with MOPP chemotherapy at three institutions (University of Pennsylvania, the Animal Medical Center, and VCA Western Veterinary Specialist and Emergency Centre) were examined. Information evaluated included patient signalment, feline immunodeficiency virus/feline leukemia virus status, anatomic location(s) of lymphoma, prior protocols (type and number), MOPP doses, MOPP response, remission duration, hematologic and biochemical parameters, and owner-reported adverse effects. RESULTS: Overall, 70.3% of cats responded to MOPP chemotherapy. Among the responders, the median remission duration was 166 days. The most common adverse effects were neutropenia and gastrointestinal upset, which were reported in 18.4% of cats. In 55.3% of cats, no adverse effects were reported. In total, 30.8% of responders continued to respond 6 months following the initiation of MOPP, and 15.4% maintained a response 1 year after starting MOPP. CONCLUSIONS AND RELEVANCE: MOPP is a safe protocol for the treatment of relapsed or refractory feline lymphoma, with a promising overall response rate and median remission time.

Clinical outcomes, ultrastructure and immunohistochemical features of canine high-grade olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a rare intranasal neoplasm in both dogs and humans. Similar clinical presentation and overlapping histologic and immunohistochemical features of ONB with other intranasal neoplasms can make diagnosis and treatment of intranasal neoplasia challenging. Furthermore, in part because of their rarity, there is a lack of reporting on therapeutic regimen for these neoplasms. In humans, initial debulking surgery is usually followed by radiation therapy. Here we report on the histologic, immunohistochemical, and ultrastructural characteristics of canine ONB and report on the clinical progression of cases treated with radiation therapy. In all nine canine ONB examined here, neoplastic cells were arranged in a lobular manner amidst a prominent neurofibrillary matrix and had features consistent with Grade III (high grade) ONB. The neoplastic cells demonstrated positive immunohistochemical staining for TuJ-1, a Class III beta-tubulin neuronal cytoskeletal protein, and variable staining for other markers, including chromogranin, synaptophysin, AE1/AE3 and MAP2. The longest surviving case was treated with a regimen similar to that used in humans, consisting of debulking surgery followed by definitive radiation therapy. Our study found that TuJ-1 is a useful marker for ONB and that radiation therapy, even in cases of advanced disease, may result in prolonged survival.