RESUMEN
INTRODUCTION: Paraneoplastic cerebellar degeneration (PCD) is a rare set of neurological disorders arising from tumor-associated autoimmunity against antigens within the cerebellum. Anti-Purkinje cell cytoplasmic antibody 1 (PCA-1), or anti-Yo, is the most commonly linked antibody and is classically associated with breast and ovarian cancers. METHODS: Medical records of patients at our institution who developed PCA-1 associated PCD were reviewed. Clinical information, including cancer history, cancer-directed treatment, and serum and CSF titers of PCA-1 antibody were extracted. CASES: We report a series of cases of PCA-1 associated PCD in patients with known breast or ovarian cancer diagnosis not receiving immunotherapy. These cases highlight aspects of PCA-1 paraneoplastic syndrome such as triggering by cytotoxic chemotherapy or surgery, the possibility of tumor recurrence and the association with development of a second cancer. DISCUSSION: Diagnosis of the syndrome requires neurological workup with lumbar puncture (LP) with cerebrospinal fluids (CSF) studies, serum and CSF paraneoplastic antibody panel, and neuroimaging. Inpatient admission for prompt workup and initiation of treatment is recommended. Treatment most commonly includes immunosuppression with corticosteroids, plasmapheresis, and/or intravenous immune globulin (IVIG); however, we postulate that other immune modulating treatments may warrant consideration. CONCLUSION: These cases highlight the need for early recognition of the syndrome in patients receiving nonimmune based chemotherapy, for prompt workup and treatment.
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Neoplasias Ováricas , Degeneración Cerebelosa Paraneoplásica , Anticuerpos Antineoplásicos , Antígenos de Neoplasias , Autoanticuerpos , Cerebelo , Femenino , Humanos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/terapia , Degeneración Cerebelosa Paraneoplásica/etiología , Degeneración Cerebelosa Paraneoplásica/terapiaRESUMEN
PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.
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Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias , Animales , Humanos , Ratones , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Mutación con Pérdida de Función , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Immune checkpoint therapy (ICT) prolongs survival in subsets of patients with cancer but can also trigger immune-related adverse events (irAEs) requiring treatment discontinuation. Recent studies have investigated safety of ICT rechallenge after irAEs, and evidence suggests that rechallenge may be associated with improved antitumor responses. However, data are limited on response duration after ICT rechallenge, particularly after severe irAEs. OBJECTIVE: To evaluate safety and efficacy of ICT rechallenge after moderate-to-severe irAEs in patients with renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer. METHODS: In this retrospective cohort study, medical records from September 25, 2013, to June 1, 2020, for patients with genitourinary (GU) cancers at MD Anderson Cancer Center who were rechallenged with the same or different ICT following irAEs were reviewed. Demographics, ICT exposure, irAEs (grade and treatment), ICT discontinuation or rechallenge, rates of subsequent irAEs (new or recurrent) and antitumor activity (objective response rates and response duration) were reviewed. RESULTS: Sixty-one patients with RCC, UC, and prostate cancer were rechallenged with ICT after experiencing 105 total irAEs. Objective response rates after rechallenge, that is, upgrade in response, were 14% in RCC (4/28), 21% in UC (3/14), and 0% in prostate cancer. All seven patients who achieved upgrade in response had initial grade 2 or 3 irAEs. Responses were durable among these seven patients, with median radiographic progression-free survival not reached (range: 3.7-66.4 months) as of the March 8, 2021, data cut-off (median follow-up 40.9 months (95% CI 35.3 to 46.5)). All achieved complete response except one patient who was lost to follow-up. The rate of subsequent grade 3 or 4 irAEs after rechallenge was 30%, with no fatal irAEs. The rate of recrudescence of the same irAE was 26% (16/61). 54% of patients received corticosteroids (33/61), and 21% received targeted immunosuppression (13/61) for the initial irAEs. CONCLUSIONS AND RELEVANCE: ICT rechallenge after moderate-to-severe irAEs was associated with deep and durable responses in a subset of patients with RCC and UC, with acceptable safety and no fatal events. Strategies to enable ICT resumption after moderate-to-severe irAEs, such targeted immunosuppression, warrant further study.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/métodos , Neoplasias Urogenitales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Targeted drug deliveries as well as high resolution imaging of cancerous tissues and organs via specific cancer cell markers have become important in chemotherapeutic interventions of cancer treatment. Short peptides such as RGD and NGR are showing promising results for targeted drug delivery and in vivo imaging. We have applied on resin Huisgen's 1,3-dipolar cycloaddition to synthesize new cyclic RGD and NGR peptide analogs. Preliminary binding assays of these new analogs by fluorescence polarization indicates specific binding to purified CD13 (Aminopeptidase N) and cell lysates from MCF-7 and SKOV-3 cancer cell lines.
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Péptidos Cíclicos/síntesis química , Resinas Sintéticas/química , Antígenos CD13/química , Antígenos CD13/metabolismo , Línea Celular Tumoral , Química Clic , Ciclización , Portadores de Fármacos/química , Polarización de Fluorescencia , Humanos , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/química , Unión ProteicaRESUMEN
Peptide nucleic acids (PNAs) have gained much interest as molecular recognition tools in biology, medicine and chemistry. This is due to high hybridization efficiency to complimentary oligonucleotides and stability of the duplexes with RNA or DNA. We have synthesized 15/16-mer PNA probes to detect the HER2 mRNA. The performance of these probes to detect the HER2 target was evaluated by fluorescence imaging and fluorescence bead assays. The PNA probes have sufficiently discriminated between the wild type HER2 target and the mutant target with single base mismatches. Furthermore, the probes exhibited excellent linear concentration dependence between 0.4 to 400 fmol for the target gene. The results demonstrate potential application of PNAs as diagnostic probes with high specificity for quantitative measurements of amplifications or over-expressions of oncogenes.
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Genes erbB-2 , Sondas Moleculares , Ácidos Nucleicos de Péptidos/química , Secuencia de Bases , Cartilla de ADN , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Propiedades de SuperficieRESUMEN
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active against NB cell lines at < or =10 microM concentration. More interestingly, 17 compounds are active at < or =1 microM concentration, and they act through a wide spectrum of diverse mechanisms such as mitotic inhibition, topoisomerase inhibition, targeting various biological pathways, and unknown mechanisms. The majority of these active compounds also induced caspase 3/7 by more than 2-fold. Of these 17 active compounds against NB cell lines at sub-micromolar concentration, eleven compounds are not currently used to treat NB. Among them, nine are FDA approved compounds, and three agents are undergoing clinical trials for various malignancies. Furthermore, we identified four agents active against these NB cell lines that have not yet been tested in the clinical setting. Finally we demonstrated that Cucurbitacin I inhibits neuroblastoma cell growth through inhibition of STAT3 pathway. These drugs thus represent potential novel therapeutic agents for patients with NB, and further validation studies are needed to translate them to the clinic.