Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most ...cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.
Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary ...endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.
Squamous-cell lung cancer is one of the most prevalent subtypes of lung cancer worldwide and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer ...patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 gene and mutations of the discoidin domain receptor 2 gene as potential novel targets for the treatment of squamous-cell lung cancer patients. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.
DailyDose is a smart-phone decision support system developed at Oregon Health & Science University that uses Dexcom G6 CGM and Medtonic’s InPen. The app calculates insulin doses using CGM value and ...trend, insulin-on-board, carbohydrate amount, and exercise information. Insulin dosing and carbohydrate intake recommendations before and after exercise are adjusted according to the 2017 consensus statement by Riddell et al. known as the PEAK Guidelines. Twenty-four adults with T1D, using multiple daily injections of insulin at baseline, completed a two-week run-in period then used the DailyDose intervention for 8 weeks. Participants completed 3 at-home exercise sessions per week, one aerobic exercise video and two other sessions of their choice. We examined the impact of the use of PEAK guidelines on glucose outcomes during exercise comparing 176 exercise sessions done during run-in and 471 sessions done during the intervention period. Glucose outcomes were assessed from start of exercise to 4 hours after the start or until either a meal was consumed, insulin dosed or new exercise session initiated. Mixed effects analysis was used to determine significance of the intervention on glucose outcomes. The nadir of the glucose was lower for the run-in compared with the intervention (120.6 vs. 130.9 mg/dL, P=.012) . Change in glucose from the start of exercise to the nadir was 58.0 for the run-in versus 46.9 for the intervention period (P=.016) . Time in hyperglycemia (>180mg/dL) during the exercise periods trended toward being lower during the intervention (43.8% run-in, 35.0% intervention, P=.059) , as did time in range of 70-180 mg/dL, (54.2% run-in, 62.2% intervention, P=.081) . There was no difference in time in hypoglycemia. Data suggest that use of PEAK within a decision support app can help prevent more severe glucose drops during and after exercise with a trend toward improving time in range.
Disclosure
L.M.Wilson: n/a. S.M.Oganessian: None. D.Branigan: None. V.Gabo: None. J.H.Eom: None. J.El youssef: None. K.Winters-stone: None. J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. F.H.Guillot: Stock/Shareholder; Pacific Diabetes Technologies. N.S.Tyler: None. T.Kushner: Consultant; Tandem Diabetes Care, Inc. A.Z.Espinoza: None. C.M.Mosquera-lopez: None. J.Pinsonault: None. R.Dodier: None.
Funding
The Leona M. and Harry B. Helmsley Charitable Trust (Grant 2018PG-T1D001) , OHSU Medical Research Foundation, Supplies provided by Dexcom
DailyDose is a decision support system developed at Oregon Health & Science University designed for people with T1D on MDI to improve glycemic control. It connects with Dexcom G6 and Medtronic's ...InPen. DailyDose runs on a smartphone and calculates insulin doses using CGM value and trend, IOB, carbohydrate amount, and exercise information. The system analyzes CGM and insulin data and automatically provides weekly recommendations on insulin settings, such as basal insulin dose and carbohydrate ratios, based on a k-nearest neighbors algorithm. Twenty-four adults with T1D used DailyDose for 8 weeks. The primary outcome was change in % time in range (TIR, 70-180 mg/dL) on CGM comparing the two week run-in period before starting DailyDose vs. final two weeks of DailyDose use. A mixed effects model was used to determine the impact of the % of accepted recommendations on change in % TIR. Users who accepted and followed recommendations showed a mean week-to-week improvement in TIR of 2.0% (Figure) . The mixed effects model shows week-by-week TIR increased by 7.8% when recommendations were accepted compared with not accepted (CI, 3-12%, P=.001) . Overall, there were no significant differences between TIR or time in hypoglycemia comparing the run-in period and the final two weeks of use. Further work is needed to encourage people using decision support systems to follow recommendations.
Disclosure
J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. V.Gabo: None. J.H.Eom: None. J.El youssef: None. K.Ramsey: None. T.Kushner: Consultant; Tandem Diabetes Care, Inc. K.Winters-stone: None. J.A.Cafazzo: None. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. A.Z.Espinoza: None. N.S.Tyler: None. L.M.Wilson: n/a. C.M.Mosquera-lopez: None. J.Pinsonault: None. R.Dodier: None. S.M.Oganessian: None. D.Branigan: None.
Funding
The Leona M. and Harry B. Helmsley Charitable Trust (Grant 2018PG-T1D001) .
DailyDose is a decision support system designed to provide real-time dosing advice and weekly insulin dose adjustments for adults living with type 1 diabetes using multiple daily insulin injections.
...Twenty-five adults were enrolled in this single-arm study. All participants used Dexcom G6 for continuous glucose monitoring, InPen for short-acting insulin doses, and Clipsulin to track long-acting insulin doses. Participants used DailyDose on an iPhone for 8 weeks. The primary endpoint was % time in range (TIR) comparing the 2-week baseline to the final 2-week period of DailyDose use.
There were no significant differences between TIR or other glycemic metrics between the baseline period compared to final 2-week period of DailyDose use. TIR significantly improved by 6.3% when more than half of recommendations were accepted and followed compared with 50% or fewer recommendations (95% CI 2.5%-10.1%,
= 0.001).
Use of DailyDose did not improve glycemic outcomes compared to the baseline period. In a post hoc analysis, accepting and following recommendations from DailyDose was associated with improved TIR.
NCT04428645.
During the last decade, high-throughput technologies including genomic, epigenomic, transcriptomic and proteomic have been applied to further our understanding of the molecular pathogenesis of this ...heterogeneous disease, and to develop strategies that aim to improve the management of patients with lung cancer. Ultimately, these approaches should lead to sensitive, specific and noninvasive methods for early diagnosis, and facilitate the prediction of response to therapy and outcome, as well as the identification of potential novel therapeutic targets. Genomic studies were the first to move this field forward by providing novel insights into the molecular biology of lung cancer and by generating candidate biomarkers of disease progression. Lung carcinogenesis is driven by genetic and epigenetic alterations that cause aberrant gene function; however, the challenge remains to pinpoint the key regulatory control mechanisms and to distinguish driver from passenger alterations that may have a small but additive effect on cancer development. Epigenetic regulation by DNA methylation and histone modifications modulate chromatin structure and, in turn, either activate or silence gene expression. Proteomic approaches critically complement these molecular studies, as the phenotype of a cancer cell is determined by proteins and cannot be predicted by genomics or transcriptomics alone. The present article focuses on the technological platforms available and some proposed clinical applications. We illustrate herein how the "-omics" have revolutionised our approach to lung cancer biology and hold promise for personalised management of lung cancer.
PDF
