Gradalis (United States)

Gene fusions represent important oncogenic driver mutations resulting in aberrant cellular signaling. In up to 17% of all solid tumors at least one gene fusion can be identified. Precision therapy targeting fusion gene signaling has demonstrated effective clinical benefit. Advancements in clinically relevant next-generation sequencing and bioinformatic techniques have enabled expansion of therapeutic opportunity to subpopulations of patients with fusion gene expression. Clinically, tyrosine inhibitors have shown efficacy in treating fusion gene expressing cancers. Fusion genes are also clonal mutations, meaning it is a personal cancer target involving all cancer cells of that patient, not just a subpopulation of cancer cells within the cancer mass. Thus, both fusion signal disruption and immune signal targeting are effective therapeutic directions. This review discusses fusion gene targeting, therapeutic resistance, and molecular biomarkers.

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi's), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi's have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in BRCA wild-type, homologous recombination proficient (HRP) cancers. Therefore, attempts have been made at combination therapy involving PARPi to improve patient outcomes. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated underwhelming results involving ovarian cancer. Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.

A importância dos negócios sociais vem crescendo nas últimas décadas (Ande, 2016) a ponto de serem hoje uma parte relevante do cenário de investimentos de muitas economias, até mesmo de países em desenvolvimento como o Brasil.Essas organizações são percebidas como uma forma importante de lidar com questões sociais e ambientais de forma economicamente sustentável por meio do mecanismo de mercado.No ecossistema que surgiu em torno dos negócios sociais, as aceleradoras sociais são atores importantes que podem ampliar o número ou potencializar o desenvolvimento de negócios sociais.Governos, multinacionais e a sociedade estão interessados em entender como estas funcionam, pois eles podem ter um papel importante na geração de impacto socioambientais.Este trabalho usa uma abordagem qualiquant por meio de um estudo multicaso (Eisenhardt,1989) por meio de modelos de simulação para entender quais são as variáveis-chave para o desenvolvimento das aceleradoras.Priorizouse compreender como essas organizações podem vir a ser financeiramente autossustentáveis.Os dois casos explorados por meio de modelos elaborados com o software Vensim permitiram compreender diferentes possibilidades para os casos analisados.Encontrou-se dificuldade em sustentar financeiramente um programa de aceleração por meio de receitas das startups aceleradas.Embora tenham sido simulados cenários em que isso seja possível, o tempo para as startups saírem ou gerarem receita, dificultam que estas cubram os custos do programa.Mesmo assim, alguns empreendedores conseguem acelerar

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care-such as bevacizumab and the immune CPIs-and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.

Spinocerebellar ataxias (SCA) have an average worldwide prevalence of 2.7 cases per 100,000 individuals and great geographic variability. The present study aimed to identify and characterize SCA in the state of Alagoas in order to contribute to the epidemiological and clinical profile of SCA and to stimulate the development of strategies to detect people with SCA in regions without epidemiological data. From June 2018 to August 2021, we carried out active search strategies for people with a diagnosis or clinical suspicion of SCA and applied a clinical and molecular evaluation protocol. We identified 73 people with SCA, configuring a minimum estimated prevalence of 2.17 cases per 100,000 inhabitants, distributed as 75.3% with SCA3, 15.1% with AEC 7, 6.8% with AEC1 and 2.7% with AEC 2. SCA3 and SCA7 analysis showed age at onset and clinical features congruent with other studies; predominance of SCA3 subphenotype 2; gait alterations as the main initial manifestation and, in people with SCA7, accompanied by reduced visual capacity; inverse correlation between age at onset and number of expanded CAG; positive correlation between severity and disability scales and duration of illness; and that most affected people are not engaged in a rehabilitation program and there are large numbers of asymptomatic people at risk of developing AEC. In this study, we show how simple collaborative strategies can enhance the detection capacity of affected people and demonstrate that Alagoas has a minimum estimated prevalence of AEC similar to the world average prevalence.

Background: Small-cell carcinoma of the breast is a rare disease with little research outlining molecular targets or optimal therapeutic management. We summarize a young female patient with poorly differentiated high-grade carcinoma with neuroendocrine features/small-cell carcinoma. Case presentation: A 31-year-old female presented with a large left breast mass. Initial biopsy revealed small-cell, triple-negative breast carcinoma. Treatment consisted of cisplatin and etoposide but was poorly tolerated and discontinued after one cycle. Combination abraxane/atezolizumab resulted in transient partial response in tumor size with 7 months of progression-free stability. Worsening metastatic disease was found 8months after initial biopsy on radiologic studies and the patient expired 10months after initial biopsy. Conclusion: Transient benefit in response to combination abraxane/atezolizumab was demonstrated.

BackgroundThe PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies.MethodsM2698 was administered as monotherapy (escalation, 15–380 mg daily; food effect cohort, 240–320 mg daily) and combined with trastuzumab or tamoxifen.ResultsOverall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively.ConclusionsM2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance.Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.

Coronavirus disease 19 (COVID-19) is an infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The pandemic spread of SARS-CoV-2 has resulted in significant health, economic, and social ramifications. There are no U.S. Food and Drug Administration (FDA)-approved prophylactic or therapeutic treatment options for COVID-19. This puts unprecedented product development pressure on the medical science community to define treatment options. Additionally, in the United States of American (USA) further regulatory and quality assurance pressures impact the FDA. The regulatory therapeutic development process is complex as it relates to product mechanism, toxicity profile, and level of efficacy. The advert of a worldwide pandemic however, advanced efficiencies within many of the regulatory agencies worldwide in order to facilitate COVID-19 treatment option development within the USA. Clinical drug development pathways can include several established approaches: investigational new drug (IND), expanded access IND, emergency IND, treatment IND, and emergency use authorization (EUA). Remdesivir, an investigational drug, and hydroxyloroquine, an FDA-approved drug for autoimmune diseases, were the two early potential therapies. This review article examines the expedited FDA review process for remdesivir and hydroxychloroquine, and analyzes data and results from early clinical studies of both drugs.

3017 Background: Metastasis to the peritoneal cavity is associated with end-stage disease in many cancers, including OC and CRC, both of which exhibit poor responses to checkpoint inhibitors. Locoregional treatment with oncolytic viruses may be used to improve the efficacy of checkpoint inhibitors at both treated and distant tumor sites. This study evaluates the combination of IP-administered ONCOS-102, an oncolytic adenovirus encoding for granulocyte macrophage colony stimulating factor (GMCSF), with systemic durvalumab, an anti PD-L1 antibody, in patients with peritoneal disease who have histologically confirmed OC or metastatic CRC and have failed prior standard therapies. Methods: This ongoing Phase 1/2, open-label study (NCT02963831) evaluates safety and antitumor/biologic activity of durvalumab (1500 mg IV, every 4 weeks x 12) + ONCOS-102 (IP, weekly x 6); cyclophosphamide is given pre first ONCOS-102 dose. Phase 1 uses a 3+3 design to evaluate the ONCOS-102 dose (1 or 3 x 1011 VP) to be given with durvalumab. Phase 2 evaluates the activity of the combination using Simon’s 2-stage MINIMAX design. Safety, response rate by RECIST 1.1, and immunological effects in tumors were evaluated for Phase 1; the current abstract reports on the phase 1 results. Results: Enrollment opened 7 Sep 2017; data cutoff, 1 Nov 2019. There were 17 patients treated in Phase 1: 8 CRC, 9 ovarian; 94% female; median age, 56 [37-77] years; ECOG PS0, 47%; ECOG PS1, 53%. There were no DLTs. Grade 3 treatment-related AEs included hypokalemia (n = 2); anemia, myocarditis, increased GGT, and influenza like illness (n = 1 each). There were 4 deaths due to PD. One patient had durable confirmed partial response and remains on treatment &gt; 1 year; 4 patients had stable disease as best overall response. Two patients remained on treatment at data cutoff. Analysis of pre- and on-treatment tumor biopsies revealed changes in the tumor-infiltrating immune cells and PD-L1 expression, including an increase in tumor-infiltrating CD8 T cells in 5 of 11 evaluable patients. Conclusions: Combination of durvalumab and IP ONCOS-102 was safe, and no DLTs were observed. Preliminary analyses demonstrate evidence of biologic and clinical activity. Phase 2 enrollment is ongoing. Clinical trial information: NCT02963831 .