Trials For Treatment Of Cancer Research Articles

Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials

Distant recurrence in women with oestrogen receptor-positive early breast cancer persists at a constant rate for more than 20 years after diagnosis, with little equivalent data for oestrogen receptor-negative breast cancer. Using the database of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) we investigated rates of distant breast-cancer recurrence in oestrogen receptor-positive and oestrogen receptor-negative tumours and trends in outcomes over time. In this pooled analysis of randomised controlled trial data, patients in the EBCTCG database of more than 650 000 women in trials of treatment for early-stage breast cancer were screened for eligibility. Women were eligible if they were enrolled between 1990 and 2009 and newly diagnosed with oestrogen receptor-positive breast cancer and scheduled for at least 5 years of endocrine therapy, or oestrogen receptor-negative disease, and if they were younger than 75 years at diagnosis, had a tumour diameter of 50 mm or less, and fewer than ten positive axillary lymph nodes, and no evidence of distant metastases at entry. Trial of neoadjuvant therapy, or those in which adjuvant therapy was unclear, and women with oestrogen receptor-negative, progesterone receptor-positive disease, or those for whom outcome or baseline data were missing were excluded. The primary outcome was time to first distant recurrence as defined by each trial, ignoring any locoregional recurrence or contralateral breast cancer. 10-year risks of distant recurrence by period of diagnosis were compared using Cox regression adjusted for patient and tumour characteristics, trial, and assigned treatment. Of the 652 258 women with early breast cancer in the EBCTCG database on Jan 17, 2023, patient-level data were available from 151 randomised trials that included 155 746 women. Rates of distant tumour recurrence improved similarly in women with oestrogen receptor-positive and oestrogen receptor-negative tumours. 80·5% of the improvement for oestrogen receptor-positive disease and 89·8% of the improvement for eostrogen receptor-negative disease was explained by changes in patient and tumour characteristics and improved treatments, but remained significant (p<0·0001). More recently diagnosed patients were more likely to have node-negative disease. 10-year distant recurrence risks during 1990-99 versus 2000-09 were as follows: for node-negative disease, 10·1% versus 7·3% for oestrogen receptor-positive disease and 18·3% versus 11·9% for oestrogen receptor-negative disease; for disease with one to three positive nodes, 19·9% versus 14·7% for oestrogen receptor-positive disease and 31·9% versus 22·1% for oestrogen receptor-negative disease; and for disease with four to nine positive nodes, 39·6% versus 28·5% for oestrogen receptor-positive disease and 47·8% versus 36·5% for oestrogen receptor-negative disease. After adjustment for therapy, rates were reduced by 25% (oestrogen receptor-positive disease) and 19% (oestrogen receptor-negative disease) after 2000 versus the 1990s, with similar improvements observed in oestrogen receptor-positive disease beyond 5 years. Most of the improvement in trial outcomes is explained by a greater proportion of women with lower-risk disease entering trials and improved adjuvant treatment. After adjustment, women diagnosed since 2000 have about a fifth lower rate of distant recurrence than the 1990s. Long-term risks of distant recurrence for oestrogen receptor-positive disease remain, but are about a tenth lower now than in our previous report. Cancer Research UK, UK Medical Research Council.

State of Geographic Access to Cancer Treatment Trials in the United States: Are Studies Located Where Patients Live?

In this study, we describe the geographic distribution of US cancer treatment trials to identify disparities and opportunities for targeted improvements in access to research for people with cancer. US-based phase I-III cancer treatment trials registered on ClinicalTrials.gov were tabulated for the years they were open to enrollment (2017-2022), overall and by county, and supplemented with data from the US Census Bureau, National Cancer Institute, Centers for Disease Control and Prevention, and US Department of Agriculture. We evaluated geographic differences in trial availability. We assessed 5-year trends in trials per capita and mapped 1-hour drive time areas around sites. A total of 6,710 trials were open to enrollment in 2022 across 1,836 sites. Trials increased by 4%, whereas sites decreased by 3% annually per capita from 2017. Seventy percent of US counties had no reported active trials in 2022 (2,211/3,143), representing 19% of people age ≥55 years. Eighty-six percent of nonmetropolitan counties had no trials versus 44% of metropolitan counties. Trial availability varied by county-level cancer mortality and social vulnerability (an index derived from demographic and socioeconomic data from the US Census). Eighteen percent of counties without trials had oncologist care sites (n = 618). Notably, 26% of people age ≥55 years lived beyond an hour drive of a site with ≥100 trials. Most US counties have limited to no trial offerings, a disparity magnified in counties that are nonmetropolitan, with high social vulnerability, and with high cancer mortality. Effort to facilitate diverse site participation is needed to promote equitable access to trials and to ensure patients participating in trials match the characteristics of patients who will receive interventions once approved. Counties with oncology care sites but no trials provide potential expansion areas.

Blue-button: A tool for institution-agnostic, EHR-integrated regional clinical trial matching.

65 Background: Research indicates that most people with cancer are willing to enroll in clinical trials when offered the chance, but only 7% actually participate in cancer treatment trials. Barriers to screening and enrollment include time and effort for providers to screen patients for trials, and lack of awareness of available regional trials. Stakeholders recommended creation of free, automated screening tools and processes integrated into provider workflows, directly interfacing with site electronic health records (EHRs), that would search for regional trial eligibility. The need for such tools was independently identified in a large national survey of oncology providers. Methods: The Blue-button tool was developed to automatically identify relevant, regional clinical trials. A collaboration between ACS CAN and MITRE, a not-for-profit organization working in the public interest, created the tool’s functionality. Clinical workflow and research protocol were developed in collaboration with University of Texas Southwestern Simmons Comprehensive Cancer Center. This SMART-on-FHIR application works within existing EHR systems by automatically extracting and sending limited, deidentified patient data elements to third-party trial matching services via the FHIR mCODE standard, a core set of non-proprietary, open-source structured data elements that establishes minimum standards for the structure and content of oncology data in health records. Potential trial matches within a specified radius of the practice are returned in a standard format using the FHIR Research Study resource. Results: Blue-button extracts limited patient data from EHR and provides it in an interface allowing users to update data before sending to trial matching services. Only non-identifiable information is sent to the external clinical trial matching services, which then return prescreen trial matches for manual review to confirm patient eligibility. Thus, with a few clicks in a medical record, the tool quickly identifies comprehensive trial availability within a specified distance of the patient’s location. When used by providers, Blue-button reduces the manual burden that often prevents consideration of clinical trials and identifies regional opportunities beyond the treating institution. Conclusions: Successful feasibility testing demonstrated the effectiveness of automated regional trial screening as a model. We have launched a clinical trial at two sites to assess the effectiveness of the Blue-button tool with patients in healthcare settings. We expect patient enrollment to continue through part or all of 2025. This trial of the Blue-button tool will provide additional information on provider accessibility and uptake and will demonstrate whether EHR-integrated regional trial screening leads to increased opportunities and enrollment in cancer clinical trials. Clinical trial information: NCT05885880 .

A randomized trial of aerobic exercise in colorectal cancer: Rationale, design, recruitment, and exercise adherence results

BackgroundPhysical activity is associated with improved disease-free survival in colorectal cancer survivors. This report describes the purpose, design, recruitment, and exercise adherence results of the National Cancer Institute (NCI)-sponsored Exercise and Colorectal Cancer Treatment (EXACT) trial. MethodsThe primary objective of the EXACT trial is to determine if randomization to 150 min per week of moderate-intensity aerobic exercise reduces systemic inflammation among stage I-III colorectal cancer survivors compared with a waitlist control group over 12 weeks. Participants were provided with an in-home treadmill and heart rate monitor. Characteristics associated with randomization were identified using χ2 or Fisher's exact test for categorical variables and t-tests or analysis of covariance (ANCOVA). Exercise adherence was calculated as the total minutes exercised by total minutes prescribed. ResultsBetween August 2019 and February 2023, 3082 colorectal cancer survivors were invited to participate, 89 were screened, and 60 were randomized to the study protocol. Younger age (P = 0.02), female sex (P = 0.002), white race (P = 0.01), proximal time since tumor resection (P = 0.02), and regional tumor stage (P < 0.001) were associated with study participation. Average exercise adherence was 92.2 % (95 % CI: 85.5, 98.8) and all study participants achieved ≥80 % exercise adherence. Endpoint data collection was completed for all participants in May 2023. ConclusionThe results from the EXACT trial will characterize the changes that occur from exercise to advance our understanding of the biological mechanisms by which exercise may prevent tumor recurrence and death in colorectal cancer survivors.

The cost of doing business: Drug costs in federally sponsored cancer clinical trials.

10 Background: Federally sponsored cancer clinical trials (FS-CCTs) address a broad set of clinical cancer research questions that are avoided by industry sponsors, including combining treatment modalities, examining whether approved drugs may work in other cancers, or examining de-escalation therapy. FS-CCTs routinely extend the lives of patients with cancer and inform treatment guidelines. However, FS-CCTs must often be conducted in partnership with industry sponsors since the cost of drugs is high and cannot be paid for by the government. This limits the independence of FS-CCTs. We aimed to examine the drug costs for trials with federal sponsorship. Methods: We included all US-based cancer treatment trials registered in ClinicalTrials.gov that examined pharmaceuticals and/or biological products and started from 2018-2022. Trials with any NIH or other federal sponsorship (as the sole, lead, or other sponsor) were included. Drug names and number of enrollments per arm and drug were extracted from ClinicalTrials.gov and study protocols. The Wholesale Acquisition Cost (WAC) was obtained from IBM Micromedex RED BOOK (2023) by matching the product name, dose strength and administration route. The product acquisition cost (“cost”) per trial was computed by summing the WAC for each drug and multiplying by the number of enrollments. Results: Overall, N=1020 trials were examined (phase I = 343, phase II = 611, phase III = 66). The mean (median) drug costs were $53.9 million (m) ($7.4m) overall, including $73.8m ($19.8m), $47.2m ($8.7m), and $44.7m ($5.8m) for trials solely sponsored, led by, or with secondary/tertiary participation by federal sponsors, respectively. Trial-level drug costs were $19.2m ($3.6m), $51.9m ($9.4m), and $244.9m ($38.8m) for phase I, II, and III trials, respectively. Drug costs were much greater for trials involving immune and/or targeted therapies ($60.1m [$11.4m]) than those with conventional chemotherapies ($30.8m [$1.5m]). In the subset of n=128 phase 2 or 3 comparative trials, drug costs were $97.7m ($21.8m) for experimental arms and $24.1m ($1.4m) for control arms. Conclusions: The costs for drugs in FS-CCTs were very high, especially for the experimental arms, highlighting the necessity for federally sponsored researchers to collaborate with industry partners to conduct trials. Drug costs for immune and/or targeted therapies were higher yet, suggesting that the cost burden to conduct trials for federal sponsors may continue to increase. These findings also suggest that systemwide costs for cancer drugs in clinical practice will continue to increase substantially. These results have implications for how FS-CCTs are designed and conducted, since the necessity of collaboration between federal and industry sponsors likely limits the independence of federal research. Future public policy efforts should focus on mechanisms for independent investigation of new pharmacologic agents.

Abatement of the Survival Cliff in Older Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma in the United States.

Purpose: In 2018, a "survival cliff" in the United States was identified among older adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). This study reassessed the cliff and associated putative causes. Methods: Survival data were obtained using the U.S. Surveillance Research Program, National Cancer Institute (NCI) SEER 22 Registries. Accrual data on cancer treatment trials conducted by the NCI cooperative groups and NCI-designated cancer centers were obtained from the NCI Cancer Therapy Evaluation Program. Trend and average percent changes and statistical significances were identified with the NCI Joinpoint Regression Program. Results: A previous cliff-like decrement in the survival of 17- to 20-year-olds is no longer apparent, overall and in all racial and ethnic groups. The "survival cliff" age range was coincident with a clinical trial accrual cliff, and both diminished when more clinical trials were available to, and participated in by, young adult patients. Older AYA patients of ages 30-39 had minimal improvement in clinical trial accrual and least survival gain among the AYA age group. Conclusion: The survival cliff has abated, resulting in thousands of fewer premature deaths and tens of thousands of years of life saved-a remarkable achievement. The survival improvement may be attributed to improved clinical trial availability for and recruitment and participation of AYAs on treatment trials, application of pediatric-inspired ALL treatment regimens to AYAs, expanded national health insurance for -18 to 25 year olds, improved AYA cancer services, and a national focus on AYA oncology.

Abstract B142: The impact of financial toxicity as a barrier to access and participation in early phase clinical trials for underrepresented populations using the COST–FACIT tool

Abstract Background: ASCO has reaffirmed critical role of early phase (EP) clinical trials (CT) in cancer research and treatment that patients (pts) may achieve improvement in quality of life, experience psychological and direct medical benefits. Disparities in access and participation to CT exist and are more profoundly seen in EP CT with challenge of engaging underrepresented populations (UP) in EP CT which are often complex and only available at larger cancer centers in metropolitan areas. NCI’s Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) helped bring EP CT to UP. To determine the impact of financial toxicity (FT) as a barrier specific to EP CT participation of UP, the validated COST-FACIT tool was used to survey cancer pts undergoing treatment at the University of Kansas Cancer Center. Methods: This study was approved by our Institutional Review Board (Study 00150640). During routine scheduled visits, pts completed COST-FACIT survey on touch screen tablet. A list of validated questions on EP CT awareness, access, and willingness to participate were included in the survey. Pts responded to 12-item COST-FACIT questionnaire describing the relationship between financial stress and treatments (scale 0 to 4). The score was computed using responses captured from COST-FACIT. Based on literature, scores &amp;lt;26 were determined to be higher FT. Two-sided Fisher's Exact Tests were used to test for a significant association at an alpha level of 0.05. UP included racial and ethnic minorities, low socioeconomic status, low education, and rural. Results: Of 108 pts, 101 completed surveys. 45% identified as female and 55% as male. 11.2% 18–35 years (yrs) of age, 13.9% 36 –50 yrs, 24% 51–65 yrs and 54% &amp;gt;65 yrs. 62.4% were white, 17.8% black, and 19.8% others (Asian or Native American). 8.9% completed &amp;lt;12th grade, 23.8% completed high school, 29.7% have some college experience, 22% completed college and 16% have master’s/doctoral degree. COST-FACIT mean score was 25.7 (SD 10.4, r^2 of 0.48) showing significant financial stress. 46% of pts had scores &amp;lt;26. Pts 18-35 yrs (p=0.02), 36–65 yrs (p=0.00), had yearly incomes of &amp;gt;150,000 (p=0.02) or unaware of their yearly income (p=0.05) were more likely to have significant FT. Pts with &amp;lt; 12th grade (14.89%) or some college experiences (34.09%) were likely to have significant FT. Pts identifying as Asian or Native American were more likely to experience FT than white or black. Conclusion: Almost half of our pts suffer from significant FT creating disparities in EP CT access and participation. Data suggest ages 35-65 yrs, low levels of education, and races other than white and black experience higher levels of FT that is a barrier to EP CT participation. These data support our ongoing efforts to bring innovative EP CT to everyone including the VA and our other outreach partners with higher concentrations of UP. Data on rural and health professional shortage areas will be reported during the meeting. This project was supported in part by The University of Kansas Cancer Center P30CA168524. Citation Format: Kamiyah Hicks, Anusha Chidharla, Dinesh Pal Mudaranthakam, Hope Krebil, Issa Espinoza, Asuka Suzuki, Sam Pepper, Angelica Allen, Jill Hamilton - Reeves, Debra Sullivan, Anna Arthur, Saqib Abbasi, Anup Kasi, Rahul Parikh, Elizabeth Wulff - Burchfield, Al - Ola Abdallah, Lori Barbosa, Erin Carroll, Jennifer Heins, Tara Lin, Gary Doolittle, Weijing Sun, Joaquina Baranda. The impact of financial toxicity as a barrier to access and participation in early phase clinical trials for underrepresented populations using the COST–FACIT tool [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B142.

G6pdN126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease.

G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer. CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pdN126D) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pdN126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PDN126D+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca2+ were increased in the lungs of G6PDN126D+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PDN126D+SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7. Our results suggest G6PDN126D increases inositol triphosphate-Ca2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

Inhibition of STAT3 by 2-Methoxyestradiol suppresses M2 polarization and protumoral functions of macrophages in breast cancer

BackgroundBreast cancer metastasis remains the leading cause of cancer-related deaths in women worldwide. Infiltration of tumor-associated macrophages (TAMs) in the tumor stroma is known to be correlated with reduced overall survival. The inhibitors of TAMs are sought after for reprogramming the tumor microenvironment. Signal transducer and activator of transcription 3 (STAT3) is well known to contribute in pro-tumoral properties of TAMs. 2-Methoxyestradiol (2ME2), a potent anticancer and antiangiogenic agent, has been in clinical trials for treatment of breast cancer. Here, we investigated the potential of 2ME2 in modulating the pro-tumoral effects of TAMs in breast cancer.MethodsTHP-1-derived macrophages were polarized to macrophages with or without 2ME2. The effect of 2ME2 on macrophage surface markers and anti-inflammatory genes was determined by Western blotting, flow cytometry, immunofluorescence, qRT‒PCR. The concentration of cytokines secreted by cells was monitored by ELISA. The effect of M2 macrophages on malignant properties of breast cancer cells was determined using colony formation, wound healing, transwell, and gelatin zymography assays. An orthotopic model of breast cancer was used to determine the effect of 2ME2 on macrophage polarization and metastasis in vivo.ResultsFirst, our study found that polarization of monocytes to alternatively activated M2 macrophages is associated with the reorganization of the microtubule cytoskeleton. At lower concentrations, 2ME2 treatment depolymerized microtubules and reduced the expression of CD206 and CD163, suggesting that it inhibits the polarization of macrophages to M2 phenotype. However, the M1 polarization was not significantly affected at these concentrations. Importantly, 2ME2 inhibited the expression of several anti-inflammatory cytokines and growth factors, including CCL18, TGF-β, IL-10, FNT, arginase, CXCL12, MMP9, and VEGF-A, and hindered the metastasis-promoting effects of M2 macrophages. Concurrently, 2ME2 treatment reduced the expression of CD163 in tumors and inhibited lung metastasis in the orthotopic breast cancer model. Mechanistically, 2ME2 treatment reduced the phosphorylation and nuclear translocation of STAT3, an effect which was abrogated by colivelin.ConclusionsOur study presents novel findings on mechanism of 2ME2 from the perspective of its effects on the polarization of the TAMs via the STAT3 signaling in breast cancer. Altogether, the data supports further clinical investigation of 2ME2 and its derivatives as therapeutic agents to modulate the tumor microenvironment and immune response in breast carcinoma.

Is health-related quality of life sufficiently addressed in trials for breast cancer treatments? An assessment based on reimbursement opinions from the French health technology assessment body, 2009–2023

BackgroundBreast cancer treatments can impact the patients’ health-related quality of life (HR-QoL). This criterion is relevant for drug reimbursement decisions. We wanted to assess the usage of HR-QoL in health technology assessments (HTA). MethodsAll HAS (Haute Autorité de Santé, the French HTA body) opinions published between January 1, 2009 and March 31, 2023 for the reimbursement of breast cancer drugs were analysed. Results51 distinct appraisals were found during the period, corresponding to 45 product-specific indications, of which 36 (80 %) including clinical studies in which HR-QoL was an endpoint. HAS explicitly rejected HR-QoL data in 25 out of 36 (69 %) indications with such data. Rejections are justified by methodological weaknesses, including lack of adjustment for type I error inflation (n=21 indications), open-label treatment (n=7), lack of a pre-specified clinically relevant HR-QoL threshold (n=6) or missing data (n=6). Regardless of rejection status, HR-QoL results were not mentioned as a determinant of value assessment in 3/36 (8 %) instances (2/25 for rejected data). ConclusionsHR-QoL data are inconsistently present in HTA assessments of new breast cancer drugs. Their methodological quality often hinders their use in determining the drug’s value. Policy summaryA rigorous and acceptable comparative experimental framework is expected for HR-QoL assessments. More detail on the precise impact of the absence or presence of HR-QoL data in the determination of the drug’s added value could help understanding how this dimension is influential in the assessments.

Perspectives on Neoadjuvant Clinical Trial Participation for Patients with Kidney Cancer: A Survey-Based Examination

Background: Kidney cancer is amongst the deadliest genitourinary malignancies. Neoadjuvant systemic therapy has the potential to improve survival and overall outcomes in select patients. Enrolling patients in trials of neoadjuvant treatment for kidney cancer is challenging, which limits neoadjuvant treatment development. Objective: This study aims to develop a better understanding of the barriers patients face in kidney cancer clinical trial participation, with a particular focus on neoadjuvant trials for renal cell carcinoma. Methods: From 2022–2023, we recruited participants with a history of kidney cancer through a Qualtrics survey that was sent to the Kidney Cancer Association (KCA) and Kidney Cancer Cure (KCCure) mailing lists and social media pages. Patient responses on demographics, clinical information, and perspectives were evaluated. Results: Ninety-four individuals completed the survey. Eighty-one percent of respondents reported not participating in clinical trials due to not being informed about potential applicable trials. Importantly, many (76%) respondents reported that prevention of cancer return was a highly important reason to participate in clinical trials. Most respondents reported a willingness to undergo a kidney biopsy (59%), and/or additional appointments (58%) and surgery delays. Conclusions: Increased patient awareness about clinical trials with the potential to delay cancer recurrence may increase patient participation in clinical trials. Clinical trial design, including additional appointments or interventions and/or minor surgery delays are not major barriers to trial participation.

Exploring the Relationship Among Financial Hardship, Anxiety, and Depression in Patients With Cancer: A Longitudinal Study.

Financial hardship (FH) is a complex issue in cancer care, affecting material conditions, well-being, and coping behaviors. This study aimed to longitudinally examine FH, anxiety, depressive symptoms, and their associations while incorporating social determinants of health and health care cost covariates in a sample of patients diagnosed with cancer. This prospective, longitudinal cohort study analyzed data from 2,305 participants from the Northwestern University Improving the Management of Symptoms during and following Cancer Treatment trial. Outcomes assessed at baseline and at 3, 6, 9, and 12 months postbaseline included depressive symptoms, anxiety, and FH. Analysis involved random intercept cross-lagged panel models to explore between- and within-person effects, incorporating factors such as age, sex, insurance status, neighborhood area deprivation, health care charges, out-of-pocket costs, and health literacy. The cohort had a mean age of 60.7 (standard deviation [SD] = 12.7) years and was mostly female (64.9%) and White (86.2%). Correlations were found between FH and depressive symptoms (r = 0.310) and anxiety (r = 0.289). A predictive relationship was observed between FH and depressive symptoms, with baseline and 6-month depressive symptom levels predicting later FH (baseline β = .079, P = .070; 6-month β = .072, P = .081) and 9-month FH significantly predicting 12-month depressive symptoms (β = .083, P = .025), even after accounting for health care charges and out-of-pocket costs. Baseline and 9-month anxiety showed a predictive relationship with subsequent FH (baseline β = .097, P = .023; 9-month β = .071, P = .068). FH emerged as a prominent issue, with nearly half of participants experiencing some level of FH. Depressive symptoms and anxiety were related to FH. These findings underscore the need for a comprehensive approach in cancer care that concurrently addresses anxiety, depressive symptoms, and FH, recognizing their interconnected impact.

Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance.

Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional-targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance. Inhibition of CDK9 or CDK12 potently suppressed Hh signaling and tumor growth in various SMOi responsive or resistant Hh-driven tumor models. Systemic epigenomic profiling elucidated the Hh-driven super-enhancer (SE) landscape and identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the insulin-like growth factor (IGF) pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target in Hh-driven tumor models. Collectively, this study identifies SE-driven transcriptional dependencies that represent promising therapeutic vulnerabilities for suppressing the Hh pathway and overcoming SMOi resistance. As CDK9 and IRS inhibitors have already entered human clinical trials for cancer treatment, these findings provide comprehensive preclinical support for developing trials for Hh-driven cancers. Significance: Dissecting transcriptional dependencies driven by super-enhancers uncovers therapeutic targets in Hedgehog-driven cancers and identifies strategies for overcoming resistance to smoothened inhibitors.

Relationships of Prodiginins Mechanisms and Molecular Structures to their Antiproliferative Effects.

The Prodiginins (PGs) natural pigments are secondary metabolites produced by a broad spectrum of gram-negative and gram-positive bacteria, notably by species within the Serratia and Streptomyces genera. These compounds exhibit diverse and potent biological activities, including anticancer, immunosuppressive, antimicrobial, antimalarial, and antiviral effects. Structurally, PGs share a common tripyrrolic core but possess variable side chains and undergo cyclization, resulting in structural diversity. Studies have investigated their antiproliferative effects on various cancer cell lines, with some PGs advancing to clinical trials for cancer treatment. This review aims to illuminate the molecular mechanisms underlying PG-induced apoptosis in cancer cells and explore the structure-activity relationships pertinent to their anticancer properties. Such insights may serve as a foundation for further research in anticancer drug development, potentially leading to the creation of novel, targeted therapies based on PGs or their derivatives.

Gender medicine in lung diseases

Gender-specific differences in the diagnostics and treatment must be considered for various lung diseases. In the case of pneumothorax, in addition to differences in etiology there are also relevant differences in treatment and recurrence rates between men and women. For example, to achieve low recurrence rates catamenial pneumothorax requires interdisciplinary collaboration with gynecology. The incidence of lung cancer has equalized in recent years and in addition, various gender-specific prognostic factors have become relevant. Several meta-analyses have identified female gender as apositive prognostic factor for lung cancer, in addition to the higher prevalence of various driver mutations in women. In current trials of multimodal treatment for lung cancer, gender differences in tolerability and patient outcome are already apparent. In subgroup analyses better event-free survival was observed in women, although immune-mediated adverse events were more common in women.

A PNPLA3-Deficient iPSC-Derived Hepatocyte Screen Identifies Pathways to Potentially Reduce Steatosis in Metabolic Dysfunction-Associated Fatty Liver Disease.

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.

Are community oncology practices with or without clinical research programs different? A comparison of patient and practice characteristics.

Expanding access to clinical trials in community settings is a potential approach to addressing disparities in accrual of historically underrepresented populations. However, little is known about the characteristics of practices that do not participate in research. We investigated differences in patient and practice characteristics of US community oncology practices with high vs low engagement in clinical research. We included patients from a real-world, nationwide electronic health record-derived, de-identified database who received active treatment for cancer at community oncology practices between November 1, 2017, and October 31, 2022. We assessed patient and practice characteristics and their associations with high vs low research engagement using descriptive analyses and logistic regression models. Of the 178 practices, 70 (39.3%) events had high research engagement, treated 57.8% of the overall 568 540 patient cohort, and enrolled 3.25% of their patients on cancer treatment trials during the 5-year observation period (vs 0.27% enrollment among low engagement practices). Practices with low vs high research engagement treated higher proportions of the following patient groups: ages 75 years and older (24.2% vs 21.8%), non-Latinx Black (12.6% vs 10.3%) or Latinx (11.6% vs 6.1%), were within the lowest socioeconomic status quintile (21.9% vs16.5%), and were uninsured or had no documented insurance (22.2% vs 13.6%). Patient groups historically underrepresented in oncology clinical trials are more likely to be treated at community practices with limited or no access to trials. These results suggest that investments to expand the clinical research footprint among practices with low research engagement could help address persistent inequities in trial representation.

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP.

We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. Though such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell context-dependent manner (in about two-thirds of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin-interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.

ERK1/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response.

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment and is linked to dementia and mental health conditions, yet no FDA-approved drugs exist to prevent it. Downregulating the mitogen-activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL, but the molecular targets and the mechanism of protection are not fully understood. Here, we tested specifically the role of the kinases ERK1/2 in noise otoprotection using a newly developed, highly specific ERK1/2 inhibitor, tizaterkib, in preclinical animal models. Tizaterkib is currently being tested in phase 1 clinical trials for cancer treatment and has high oral bioavailability and low predicted systemic toxicity in mice and humans. In this study, we performed dose-response measurements of tizaterkib's efficacy against permanent NIHL in adult FVB/NJ mice, and its minimum effective dose (0.5 mg/kg/bw), therapeutic index (>50), and window of opportunity (<48 h) were determined. The drug, administered orally twice daily for 3 days, 24 h after 2 h of 100 dB or 106 dB SPL noise exposure, at a dose equivalent to what is prescribed currently for humans in clinical trials, conferred an average protection of 20-25 dB SPL in both female and male mice. The drug shielded mice from the noise-induced synaptic damage which occurs following loud noise exposure. Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases' inhibition could be a promising strategy for the treatment of NIHL.

Impact of the COVID-19 pandemic mitigation strategies on cancer treatment trials: A meta-analysis of industry and NCI studies.

11021 Background: ASCO and Friends of Cancer Research established a task force to evaluate trial mitigation strategies allowed by US regulators during the COVID-19 pandemic, including the use of telemedicine and remote monitoring. We report the results of a meta-analysis quantifying the impact of these strategies on quality metrics and the recovery time to pre-COVID levels. Methods: We invited 41 sponsors with active US cancer treatment trials from January 2015-May 2022 to contribute deidentified trial-level aggregate data on major protocol deviations (PDs), dropouts, severe or worse toxicity (CTCAE Grade 3-5), and enrollment. We examined outcomes as proportions of participants at-risk during the pre-COVID, initial wave (IW), initial recovery (IR), and secondary recovery (SR) assessment times (Table). Multi-level beta-regression analyses were adjusted for trial phase (“early”, phases I, II, or I/II, vs. “late”, phase III) with study and sponsor as random effects. Indicator variables were used for post-COVID time periods with pre-COVID as the reference. Results: Ten sponsors (9 industry and 1 NCI Cooperative Group) contributed 82 evaluable studies: 63 early and 19 late phase trials. Among the 15,679 participants, enrollment odds decreased 64% in the IW and 45% in the IR but recovered to approximately pre-COVID levels by the SR (Table). Major PDs, dropouts, and severe or worse toxicity all had lower incidence in the IW compared to pre-COVID; these outcomes were also less frequent in IR (p&lt;.05 for each), but not in the SR (p&gt;.05 for each) compared to pre-COVID. Conclusions: Large declines in enrollment rates during the IW rebounded to pre-COVID levels by 2021-2022. We found steep reductions in the rates of reported occurrence of major PDs, dropouts, and severe or worse toxicity during the initial outbreak, which also recovered to pre-COVID levels by 2021-2022. Findings suggest pandemic-related procedural flexibility did not lead to increased reporting of PDs or dropouts and highlight how use of mitigation strategies likely corresponded with the temporary disruption to trial conduct during the pandemic’s peak. Sponsors could consider broader adaptation of trial flexibilities moving forward. [Table: see text]