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1.
medRxiv ; 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32766600

RESUMO

The relationship of SARS-CoV-2 lung infection and severity of pulmonary disease is not fully understood. We analyzed autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter- and intra- patient heterogeneity of pulmonary virus infection. There was a spectrum of high and low virus cases that was associated with duration of disease and activation of interferon pathway genes. Using a digital spatial profiling platform, the virus corresponded to distinct spatial expression of interferon response genes and immune checkpoint genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection.

2.
Clin Cancer Res ; 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571788

RESUMO

PURPOSE: Plasma genotyping may identify mutations in potentially "actionable" cancer genes, such as BRCA1/2, but their clinical significance is not well-defined. We evaluated the characteristics of somatically acquired BRCA1/2 mutations in patients with metastatic breast cancer (MBC). EXPERIMENTAL DESIGN: Patients with MBC undergoing routine cell-free DNA (cfDNA) next-generation sequencing (73-gene panel) before starting a new therapy were included. Somatic BRCA1/2 mutations were classified as known germline pathogenic mutations or novel variants, and linked to clinicopathologic characteristics. The effect of the PARP inhibitor, olaparib, was assessed in vitro, using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired BRCA1 mutation and a second patient with an acquired BRCA2 mutation. RESULTS: Among 215 patients with MBC, 29 (13.5%) had somatic cfDNA BRCA1/2 mutations [nine (4%) known germline pathogenic and rest (9%) novel variants]. Known germline pathogenic BRCA1/2 mutations were common in younger patients (P = 0.008), those with triple-negative disease (P = 0.022), and they were more likely to be protein-truncating alterations and be associated with TP53 mutations. Functional analysis of a CTC culture harboring a somatic BRCA1 mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic BRCA2 mutation showed no differential sensitivity. Across the entire cohort, APOBEC mutational signatures (COSMIC Signatures 2 and 13) and the "BRCA" mutational signature (COSMIC Signature 3) were present in BRCA1/2-mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC. CONCLUSIONS: Somatic BRCA1/2 mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline pathogenic and novel variants.

3.
Sci Rep ; 10(1): 9802, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555229

RESUMO

Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of ~85,000 cells from the fovea and peripheral retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and non-neuronal cells. Nearly all types are shared between the two retinal regions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis. We show that over 90% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and provide a foundation for investigating molecular mechanisms underlying visual processing.

4.
J Natl Cancer Inst ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32407488

RESUMO

BACKGROUND: CDK4/6-inhibitors (CDK4/6i)+endocrine therapy (ET) prolonged progression-free survival as first/second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) prognosis. Given the recent publication of overall survival (OS) data for the three CDK4/6i, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups. METHODS: We conducted a systematic literature search to select all available phase II/III randomized clinical trials of CDK4/6i+ET reporting OS data in first/second-line therapy of HR+/HER2-negative pre/postmenopausal MBC. A random effect model was applied for the analyses. Heterogeneity was assessed with I2 statistic. Subgroup analysis were performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP). RESULTS: Six studies were included in our analyses (3,421 patients). A clear OS benefit was observed in patients without (HR:0.68, 95%CI:0.54-0.85, I2=0.0%) and with visceral involvement (HR:0.76, 95%CI:0.65-0.89, I2=0.0%), with ≥3 metastatic sites (HR:0.75, 95%CI:0.60-0.94, I2=11.6%), in endocrine resistant (HR:0.79, 95%CI:0.67-0.93, I2=14.4%). and sensitive subset (HR:0.73, 95%CI:0.61-0.88, I2=0.0%), for age <65 (HR:0.80, 95%CI:0.67-0.95, I2=0.0%) and ≥65 years (HR:0.71, 95%CI:0.53-0.95, I2=44.4%), in postmenopausal (HR:0.75, 95%CI:0.66-0.86, I2=0.0%) and pre/perimenopausal setting (HR:0.76, 95%CI:0.60-0.96, I2=0.0%), as well as in CT-naïve patients (HR:0.72, 95%CI:0.55-0.93, I2=0.0%). CONCLUSIONS: CDK4/6i+ET combinations compared to ET alone improve OS independent of age, menopausal status, endocrine sensitiveness and visceral involvement, and should be preferred as upfront therapy instead of endocrine monotherapy.

5.
Proc Natl Acad Sci U S A ; 117(19): 10339-10349, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32341164

RESUMO

Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single-cell RNA sequencing (scRNAseq). From ∼24,000 single-cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa), and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma and for using model systems to assess mechanisms and potential interventions.


Assuntos
Humor Aquoso/metabolismo , Modelos Animais de Doenças , Olho/metabolismo , Glaucoma/patologia , Pressão Intraocular , Malha Trabecular/metabolismo , Transcriptoma , Animais , Biomarcadores/análise , Olho/citologia , Glaucoma/metabolismo , Humanos , Macaca fascicularis , Macaca mulatta , Camundongos , Especificidade da Espécie , Suínos
6.
Invest New Drugs ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32189093

RESUMO

Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung cancer, 5 head and neck [HNC], 5 glioblastoma multiforme, 2 breast, 14 other). Tumor samples were evaluated for EGFR protein expression by immunohistochemistry, EGFR and EGFR ligand mRNA expression by RNAseq, and results compared with outcome. Most common adverse events were infusion-related reaction (22/45; 49%) and fatigue (20/45; 44%). While most infusion reactions were grade ≤ 2, four patients experienced grade ≥3 infusion reactions. Several infusion reaction mitigation strategies were explored. Because of the high incidence of infusion reactions, the trial was stopped and the maximum tolerated dose was not reached. The last cleared dose: 6 mg/kg/cycle. Nineteen patients (42%) had stable disease; 4 remained on study >6 months. One HNC patient with increased levels of EGFR and EGFR ligands (amphiregulin, epiregulin) achieved a confirmed partial response. Pharmacokinetic analysis of losatuxizumab vedotin showed exposures appeared to be approximately dose-proportional. The high frequency of infusion reactions necessitated early closure of this trial. The detailed mitigation strategies used in this protocol for infusion-related reactions may provide beneficial information for trial design of agents with high infusion reaction rates.

7.
Cancer Discov ; 10(1): 86-103, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31601552

RESUMO

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. SIGNIFICANCE: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo-cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.This article is highlighted in the In This Issue feature, p. 1.

8.
Cancer Discov ; 10(1): 72-85, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31594766

RESUMO

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

9.
Cancer Discov ; 10(2): 198-213, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31806627

RESUMO

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161.

11.
Nat Med ; 25(9): 1415-1421, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501609

RESUMO

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , Neoplasias Gastrointestinais/sangue , Biópsia Líquida , Autopsia , Ácidos Nucleicos Livres/genética , Estudos de Coortes , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sequenciamento Completo do Exoma
12.
Clin Cancer Res ; 25(21): 6443-6451, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371343

RESUMO

PURPOSE: While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1-amplified (FGFR1+) metastatic breast cancer (MBC) remains undefined.Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR+)/HER2- MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro. RESULTS: In the clinical cohort (N = 110), we identified that patients with FGFR1+ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P = 0.005), coexisting TP53 mutations (41% vs. 21%; P = 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1+ HR+/HER2- MBC. In preclinical models, estrogen receptor-positive (ER+)/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER+ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition. CONCLUSIONS: Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER+/FGFR1+ MBC.

13.
NPJ Precis Oncol ; 3: 18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341951

RESUMO

Plasma genotyping identifies potentially actionable mutations at variable mutant allele frequencies, often admixed with multiple subclonal variants, highlighting the need for their clinical and functional validation. We prospectively monitored plasma genotypes in 143 women with endocrine-resistant metastatic breast cancer (MBC), identifying multiple novel mutations including HER2 mutations (8.4%), albeit at different frequencies highlighting clinical heterogeneity. To evaluate functional significance, we established ex vivo culture from circulating tumor cells (CTCs) from a patient with HER2-mutant MBC, which revealed resistance to multiple targeted therapies including endocrine and CDK 4/6 inhibitors, but high sensitivity to neratinib (IC50: 0.018 µM). Immunoblotting analysis of the HER2-mutant CTC culture line revealed high levels of HER2 expression at baseline were suppressed by neratinib, which also abrogated downstream signaling, highlighting oncogenic dependency with HER2 mutation. Furthermore, treatment of an index patient with HER2-mutant MBC with the irreversible HER2 inhibitor neratinib resulted in significant clinical response, with complete molecular resolution of two distinct clonal HER2 mutations, with persistence of other passenger subclones, confirming HER2 alteration as a driver mutation. Thus, driver HER2 mutant alleles that emerge during blood-based monitoring of endocrine-resistant MBC confer novel therapeutic vulnerability, and ex vivo expansion of viable CTCs from the blood circulation may broadly complement plasma-based mutational analysis in MBC.

14.
Cell Chem Biol ; 26(8): 1067-1080.e8, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31178407

RESUMO

The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6-collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic, and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/cyclin A/E-implicated in resistance to CDK4/6 inhibition-and CDK1/cyclin B. The multifaceted experimental and computational approaches described here therefore uncover underappreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.

15.
Cancer Discov ; 9(8): 1064-1079, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31109923

RESUMO

ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

16.
N Engl J Med ; 380(20): 1929-1940, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31091374

RESUMO

BACKGROUND: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. METHODS: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. RESULTS: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. CONCLUSIONS: Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Fulvestranto/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/genética , Diarreia/induzido quimicamente , Feminino , Fulvestranto/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona , Tiazóis/efeitos adversos
17.
Breast Cancer Res Treat ; 175(3): 649-658, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919166

RESUMO

PURPOSE: This study evaluated development of edema in patients receiving PI3K/mTOR/CDK4/6 targeted therapy for metastatic breast cancer (MBC). METHODS: We reviewed medical records of 160 patients receiving targeted therapy with PI3K/mTOR/CDK4/6 inhibitors to treat MBC (n = 160; 185 treatment occurrences). Clinicopathologic data, treatment details, and edema incidence were recorded. RESULTS: Edema incidence was 43.1% (69/160) overall and 25.6% (41/160) in the upper extremity ipsilateral to the treated breast. In 185 therapy regimens administered, 6.8% of patients on a PI3K inhibitor, 8.8% of patients on an mTOR inhibitor, and 9.2% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting upper extremity edema. Further, 9.1% of patients on a PI3K inhibitor, 18.8% of patients on an mTOR inhibitor, and 10.5% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting edema elsewhere in the body. Multivariate logistic regression showed that, beyond the established breast cancer-related lymphedema (BCRL) risk factors [axillary lymph node dissection (Odds Ratio (OR) 2.69, p = 0.020), regional lymph node irradiation (OR 6.47, p < 0.001), and body-mass index ≥ 30 kg/m2 (OR 3.46, p = 0.006)], a relative decrease in serum albumin after 3 months of treatment increased risk of developing edema (OR 2.07, p = 0.062). Neither duration nor type of therapy were significant risk factors for edema. CONCLUSION: PI3K/mTOR/CDK4/6 inhibitors may influence the development of edema, which may cause or exacerbate progression of BCRL in patients with MBC. The varied incidence of edema between therapeutic regimens warrants vigilant monitoring of patients treated with these therapies, especially those at high risk of developing BCRL.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Linfedema/epidemiologia , Terapia de Alvo Molecular/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Incidência , Linfedema/induzido quimicamente , Pessoa de Meia-Idade , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores
19.
Breast Cancer Res Treat ; 174(3): 605-613, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30607635

RESUMO

PURPOSE: Triple-negative breast cancers (TNBC) are often resistant to treatment with ionizing radiation (IR). We sought to investigate whether pharmacologic inhibition of Chk1 kinase, which is commonly overexpressed in TNBC, preferentially sensitizes TNBC cells to IR. METHODS: Ten breast cancer cell lines were screened with small molecule inhibitors against Chk1 and other kinases. Chk1 inhibition was also tested in isogenic KRAS mutant or wild-type cancer cells. Cellular radiosensitization was measured by short-term and clonogenic survival assays and by staining for the DNA double-strand break (DSB) marker γ-H2AX. Radiosensitization was also assessed in breast cancer biopsies using an ex vivo assay. Aurora B kinase-dependent mitosis-like chromatin condensation, a marker of radioresistance, was detected using a specific antibody against co-localized phosphorylation of serine 10 and trimethylation of lysine 9 on histone 3 (H3K9me3/S10p). Expression of CHEK1 and associated genes was evaluated in TNBC and lung adenocarcinoma. RESULTS: Inhibition of Chk1 kinase preferentially radiosensitized TNBC cells in vitro and in patient biopsies. Interestingly, TNBC cells displayed lower numbers of IR-induced DSBs than non-TNBC cells, correlating with their observed radioresistance. We found that Chk1 suppressed IR-induced DSBs in these cells, which was dependent on H3K9me3/S10p-a chromatin mark previously found to indicate radioresistance in KRAS mutant cancers. Accordingly, the effects of Chk1 inhibition in TNBC were reproduced in KRAS mutant but not wild-type cells. We also observed co-expression of genes in this Chk1 chromatin pathway in TNBC and KRAS mutant lung cancers. CONCLUSIONS: Chk1 promotes an unexpected, common phenotype of chromatin-dependent DSB suppression in radioresistant TNBC and KRAS mutant cancer cells, providing a direction for future investigations into overcoming the treatment resistance of TNBC.


Assuntos
Adenocarcinoma de Pulmão/genética , Quinase 1 do Ponto de Checagem/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Adenocarcinoma de Pulmão/terapia , Biópsia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/terapia , Células MCF-7 , Mutação , Compostos de Fenilureia/farmacologia , Pirazinas/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia
20.
Invest New Drugs ; 37(2): 271-281, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30073466

RESUMO

Background CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110ß, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities-51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.


Assuntos
Biomarcadores Tumorais/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos Orgânicos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Ratos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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