Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis. ...We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 < 100 nmol/L. IC100 (complete inhibition of proliferation) < 40 nmol/L was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase after exposure. NVP-AUY922 slowed growth of A549 (KRAS-mutant) xenografts and achieved tumor stability and decreased EGF receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR-tyrosine kinase inhibitors in the EGFR gene. These data will help inform the evaluation of correlative data from a recently completed phase II NSCLC trial and a planned phase IB trial of NVP-AUY922 in combination with pemetrexed in NSCLCs.
The role for PD-1/PD-L1 and CTLA-4 targeted immunotherapy is well outlined in the treatment of metastatic NSCLC. Increased survival benefit supports the use of these medications and the development ...of next-generation agents with improved efficacy and favorable side-effect profiles. The prevalence of immunotherapy-associated cardiotoxicity (IAC) has grown significantly over the past two years as awareness of this toxicity class has emerged. High-grade conduction disorders comprise a subset of cardiotoxicities with a high case fatality rate. We presented a case of suspected combination ipilimumab-nivolumab associated 3rd degree heart block. The onset of this event was 16 days after immunotherapy initiation. A literature review has suggested that over 75% of cases of cardiotoxicity are observed within the first 6 weeks. We present findings from an interrogation of the FDA Adverse Event Reporting System (FAERS) and provide clinical guidance for the early identification of high-risk patients.
Estrogen receptor (ER) signaling and its interaction with epidermal growth factor receptor (EGFR) is a potential therapeutic target in non–small-cell lung cancer (NSCLC). To explore ...cross-communication between ER and EGFR, we have correlated ER pathway gene and protein expression profiles and examined effects of antiestrogens with or without EGFR inhibitors in preclinical models of human NSCLC.
We evaluated 54 NSCLC cell lines for growth inhibition with EGFR inhibitors, antiestrogen treatment, or the combination. Each line was evaluated for baseline ER pathway protein expression. The majority were also evaluated for baseline ER pathway gene expression. Human NSCLC xenografts were evaluated for effects of inhibition of each pathway, either individually, or in combination.
The specific antiestrogen fulvestrant has modest single agent activity in vitro, but in many lines, fulvestrant adds to effects of EGFR inhibitors, including synergy in the EGFR-mutant, erlotinib-resistant H1975 line. ERα, ERβ, progesterone receptor-A, progesterone receptor-B, and aromatase proteins are expressed in all lines to varying degrees, with trends toward lower aromatase in more sensitive cell lines. Sensitivity to fulvestrant correlates with greater baseline ERα gene expression. Tumor stability is achieved in human tumor xenografts with either fulvestrant or EGFR inhibitors, but tumors regress significantly when both pathways are inhibited.
These data provide a rationale for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-EGFR agents in the clinic. Future work should also evaluate dual ER and EGFR inhibition in the setting of secondary resistance to EGFR inhibition.
Selumetinib (AZD6244; ARRY-142886) is a tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2 currently in clinical development. We evaluated the effects of ...selumetinib in 31 human breast cancer cell lines and 43 human non-small cell lung cancer (NSCLC) cell lines to identify characteristics correlating with in vitro sensitivity to MEK inhibition. IC(50) <1 micromol/L (considered sensitive) was seen in 5 of 31 breast cancer cell lines and 15 of 43 NSCLC cell lines, with a correlation between sensitivity and raf mutations in breast cancer cell lines (P = 0.022) and ras mutations in NSCLC cell lines (P = 0.045). Evaluation of 27 of the NSCLC cell lines with Western blots showed no clear association between MEK and phosphoinositide 3-kinase pathway activation and sensitivity to MEK inhibition. Baseline gene expression profiles were generated for each cell line using Agilent gene expression arrays to identify additional predictive markers. Genes associated with differential sensitivity to selumetinib were seen in both histologies, including a small number of genes in which differential expression was common to both histologies. In total, these results suggest that clinical trials of selumetinib in breast cancer and NSCLC might select patients whose tumors harbor raf and ras mutations, respectively.
Novel Drugs—Miscellaneous Category Hosmer, Wylie D.; Dubinett, Steven M.; Garon, Edward B.
Journal of thoracic oncology,
December 2010, 2010-December, 2010-Dec, 2010-12-00, 20101201, Letnik:
5, Številka:
12
Journal Article
Purpose
Current guidelines recommend prophylactic use of granulocyte-colony stimulating factors (G-CSF) when febrile neutropenia (FN) risk is greater than 20%. Advanced age is a risk factor for FN; ...however, little is known about the impact of other factors on the incidence of FN in an older population.
Patients and methods
We analyzed SEER-Medicare data (1994–2005) to develop and validate a prediction model for hospitalization with fever, infection, or neutropenia occurring after chemotherapy initiation for patients with breast, colorectal, prostate, and lung cancer.
Results
In multivariate analysis (
N
= 58,053) independent predictors of FN included advanced stage at diagnosis stage 2 (OR 1.29; 95% CI: 1.09–1.53), stage 3 (1.38; 95% CI: 1.19–1.60), and stage 4 (1.57; 95% CI: 1.35–1.83), number of associated comorbid conditions one condition (1.13; 95% CI: 1.02–1.28), two conditions (1.39; 95% CI: 1.22–1.57), and three or more conditions (1.81; 95% CI: 1.61–2.04), receipt of myelosuppressive chemotherapy (1.11; 95% CI: 0.94–1.32), and receipt of chemotherapy within 1 month of diagnosis 1 to 3 months (0.70; 95% CI: 0.62–0.80) and greater than 3 months (0.63; 95% CI: 0.55–0.73).
Conclusion
We created a prediction model for febrile neutropenia with first cycle of chemotherapy in a large population of elderly patients with common malignancies.
e18766
Background: Patients (pts) with thoracic cancers have a high rate of hospitalization and death from COVID-19. Smoking has been associated with increased risk for severe COVID-19. However, ...there is limited data evaluating the impact of smoking recency on COVID-19 severity in pts with cancer. We aimed to characterize the clinical outcomes of COVID-19 based on the recency of smoking in pts with thoracic cancers (TC) and all other cancers (OC). Methods: Adult pts with cancer and lab-confirmed SARS-CoV-2 and smoking history recorded in the CCC19 registry (NCT0435470) were included. Pts were stratified by cancer type (TC or OC) and further stratified into subgroups based on the recency of smoking cessation: current smoker; former smokers who quit < 1 yr. ago; 1-5 yr. ago; 6-10 yr. ago; quit > 10 yr. ago; and never smoker. 30-day all-cause mortality was the primary endpoint. Secondary endpoints were any hospitalization; hospitalization with supplemental O2; ICU admission; and mechanical ventilation. Results: From January 2020 to December 2021, 752 pts from TC group and 8,291 pts from OC group met the inclusion criteria. 78% of patients in TC group ever smoked compared to 36% patients in the OC group. In both groups, the majority of never-smokers were females (70% and 60% in TC and OC respectively). The burden of smoking and the rate of pulmonary comorbidities (PC) was higher in the TC group (PC 22-69%) compared to OC group (PC 12-26%) across all smoking strata. Overall, 30-day all-cause mortality was 21% and 11% in pts with TC and OC respectively. Former smokers who quit < 1 year ago in TC group had the highest rate of mortality and severe COVID-19 outcomes. However, in the OC group, there was no consistent trend of higher mortality or severe COVID-19 outcomes in specific subgroups based on smoking recency. Conclusions: To our knowledge this is the largest study evaluating the effect of granular phenotypes of smoking recency on COVID-19 outcomes in pts with cancer. Recent smokers who quit < 1 year ago in TC group had the highest rate of mortality and severe COVID-19. Further analysis exploring the factors (e.g., smoking pack years) associated with severe outcomes in this subgroup is planned.Table: see text
Objectives
Dichloroacetate (DCA) is a highly bioavailable small molecule that inhibits pyruvate dehydrogenase kinase, promoting glucose oxidation and reversing the glycolytic phenotype in preclinical ...cancer studies. We designed this open-label phase II trial to determine the response rate, safety, and tolerability of oral DCA in patients with metastatic breast cancer and advanced stage non-small cell lung cancer (NSCLC).
Materials and methods
This trial was conducted with DCA 6.25 mg/kg orally twice daily in previously treated stage IIIB/IV NSCLC or stage IV breast cancer. Growth inhibition by DCA was also evaluated in a panel of 54 NSCLC cell lines with and without cytotoxic chemotherapeutics (cisplatin and docetaxel) in normoxic and hypoxic conditions.
Results and conclusions
Under normoxic conditions in vitro, single-agent IC
50
was >2 mM for all evaluated cell lines. Synergy with cisplatin was seen in some cell lines under hypoxic conditions. In the clinical trial, after seven patients were enrolled, the study was closed based on safety concerns. The only breast cancer patient had stable disease after 8 weeks, quickly followed by progression in the brain. Two patients withdrew consent within a week of enrollment. Two patients had disease progression prior to the first scheduled scans. Within 1 week of initiating DCA, one patient died suddenly of unknown cause and one experienced a fatal pulmonary embolism. We conclude that patients with previously treated advanced NSCLC did not benefit from oral DCA. In the absence of a larger controlled trial, firm conclusions regarding the association between these adverse events and DCA are unclear. Further development of DCA should be in patients with longer life expectancy, in whom sustained therapeutic levels can be achieved, and potentially in combination with cisplatin.
•Patients with thoracic cancers and COVID-19 have high mortality and morbidity.•Systematic data evaluating the impact of recent anti-cancer therapies on COVID-19 outcomes in patients with thoracic ...cancers are limited.•We analyzed clinical data from patients with thoracic cancers and COVID-19 (N=927) to systematically evaluate the impact of recent anti-cancer therapies on the clinical outcomes of COVID-19 from the COVID-19 and Cancer Consortium (CCC19).•As opposed to immunotherapy or targeted therapy, recent (<3 months prior to COVID-19 diagnosis) cytotoxic chemotherapy exposure was significantly associated with COVID-19 severity.•None of the other systemic therapies or treatment modalities were significantly associated with 30-day all-cause mortality.•Baseline steroid use of 10 mg or more of prednisone equivalent was not associated COVID-19 severity and 30-day all-cause mortality.
Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.
To determine the ...association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.
This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.
Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).
The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.
The median age of the entire cohort was 65 years (interquartile range IQR, 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio aOR, 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).
This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.
ClinicalTrials.gov Identifier: NCT04354701.
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