A Call to Action: Dismantling Racial Injustices in Preclinical Research and Clinical Care of Black Patients Living with Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with dismal survival rates and limited therapeutic options. SCLC development is strongly associated with exposure to tobacco carcinogens. However, additional genetic and environmental risk factors that contribute to SCLC pathogenesis are beginning to emerge. Here, we specifically assess disparities pertaining to SCLC in Black populations. In contrast to non-small cell lung cancer, preliminary data suggest that Black individuals may actually be at a lower risk of developing SCLC relative to white individuals. This difference remains unexplained but urgently needs to be verified in larger data sets, because it could provide important new insights and approaches to understanding this recalcitrant tumor. Importantly, little biological information exists on SCLC in Black individuals, and few patient-derived preclinical SCLC models from diverse ancestries are available in the laboratory. Unfortunately, we note strikingly low numbers of Black participants in clinical trials testing new treatments for SCLC. Evidence further indicates that care for patients with SCLC may vary between communities with a large fraction of Black patients and those without. Together, these observations underscore the need to better investigate genetic, environmental, and socioeconomic factors associated with SCLC development, preclinical research, clinical care, and outcomes.

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.

Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer.

Recent clinical data in lung cancer suggests that epigenetically targeted therapy may selectively enhance chemotherapeutic sensitivity. There have been few if any studies rigorously evaluating this hypothesized priming effect. Here we describe a series of investigations testing whether epigenetic priming with azacitidine and entinostat increases sensitivity of NSCLC to cytotoxic agents. We noted no differences in chemosensitivity following treatment with epigenetic therapy in in vitro assays of viability and colony growth. Using cell line and patient derived xenograft (PDX) models, we also observed no change in responsiveness to cisplatin in vivo. In select models, we noted differential responses to irinotecan treatment in vivo. In vitro epigenetic therapy prior to tumor implantation abrogated response of H460 xenografts to irinotecan. Conversely, in vitro epigenetic therapy appeared to sensitize A549 xenografts (tumor growth inhibition 51%, vs. 22% in mock-pretreated control). In vivo epigenetic therapy enhanced the response of adenocarcinoma PDX to irinotecan. Taken together, these data do not support broadly applicable epigenetic priming in NSCLC. Priming effects may be context-specific, dependent on both tumor and host factors. Further preclinical study is necessary to determine whether, and in which contexts, priming with epigenetic therapy has potential to enhance chemotherapeutic efficacy in NSCLC patients.

Survival after community diagnosis of early-stage non-small cell lung cancer.

BACKGROUND: "Rush to surgery" among patients with worse symptoms, delays related to morbidity, and inclusion of patients with advanced disease in study populations have produced a mixed picture of importance of time to treatment to survival of non-small cell lung cancer. Our objective was to assess the contribution of diagnosis to first surgery interval to survival among patients diagnosed in the community with early-stage non-small cell lung cancer. METHODS: Patients with early-stage lung cancer (N = 174) at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins who were diagnosed and treated from 2003 to 2009 and followed through 2011 made up a prospective study of overall survival. Diagnosis to first surgery interval was examined overall, as 2 segments (referral interval and treatment interval), as short and longer intervals, and as a continuous variable. RESULTS: The majority of patients were female (55%) and aged more than 65 years (61%). The average mean referral and treatment delays were 61.2 and 5.9 days, respectively. Cox method hazard analysis revealed that older age (years) at diagnosis (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00-1.05), stage IIB (HR, 2.17; 95% CI, 1.12-4.21), large (>4 cm) (HR, 3.68; 95% CI, 1.05-12.93) or unknown tumor size (HR, 4.45; 95% CI, 1.21-16.38), and weeks from diagnosis to first surgery interval (HR, 1.04; 95% CI, 1.00-1.09) predicted worse overall survival. The threshold period of less than 42 days from diagnosis to surgery did not reach statistical significance. CONCLUSIONS: Patients seem to benefit from rapid reduction of tumor burden with surgery. Reasons for delay were not available. Nevertheless, referral delay experienced in the community is unduly long. In addition to patient choices, an unconscious patient or physician bias that lung cancer is untreatable or an inevitable consequence of smoking may be operating and needs further investigation.

The impact of insurance on access to cancer clinical trials at a comprehensive cancer center.

PURPOSE: Cancer patients at Johns Hopkins undergo insurance clearance to verify coverage for enrollment to interventional clinical trials. We sought to explore the impact of insurance clearance on disparities in access to cancer clinical trials at this urban comprehensive cancer center. EXPERIMENTAL DESIGN: We evaluated the frequency of insurance-based denial of access to cancer clinical trials over a 5-year period after initiation of a formal insurance clearance process. We used a case-control design to compare demographic and clinical parameters of patients denied or approved for clinical trials participation by their insurance company in a 3-year interval. RESULTS: From July 2003 to July 2008, insurance requests for clinical trial participation were submitted on 4,617 consented cancer patients at Johns Hopkins. A total of 628 patients (13.6%) with health insurance were denied therapeutic trial enrollment owing to lack of insurance coverage for participation. A total of 254 patients denied enrollment from 2005 to 2007 were selected for further analysis. Two-hundred sixty randomly selected patients approved for clinical trial participation served as controls. Patients approved were on average older (59.2 versus 54.9 years) than patients denied (P = 0.0001). Residents of Pennsylvania, which lacks a state law mandating cancer clinical trial coverage for residents, were overrepresented among the denied patients (P = 0.0009). No statistically significant variance in the likelihood of insurance denial was found on the basis of sex, race, stage of disease, or presence of comorbidities. CONCLUSIONS: Denial of access to therapeutic clinical trials, even among insured patients, is a significant barrier to clinical cancer research. This barrier spans racial, ethnic, and gender categories.

Geographic proximity and racial disparities in cancer clinical trial participation.

This study assessed the effects of race and place of residence on clinical trial participation by patients seen at a designated NCI comprehensive cancer center. Clinical trial accrual to cancer case ratios were evaluated using a database of residents at the continental United States seen at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins from 2005 to 2007. Place of residence was categorized into 3 nonoverlapping geographic areas: Baltimore City, non-Baltimore City catchment area, and non-catchment area. Controlling for age, sex, county poverty level, and cancer site, significant race and place of residence differences were seen in therapeutic or nontherapeutic clinical trials participation. White non-Baltimore City catchment area residents, the designated reference group, achieved the highest participation rate. Although the test of interaction (control group compared with all others) was not significant, some race-geographic area group differences were detected. In therapeutic trials, most race-place of residence group levels were statistically lower and different from reference; in nontherapeutic trials, race-specific Baltimore City groups participated at levels similar to reference. Baltimore City residents had lower participation rates only in therapeutic trials, irrespective of race. County poverty level was not significant but was retained as a confounder. Place of residence and race were found to be significant predictors of participation in therapeutic and nontherapeutic clinical trials, although patterns differed somewhat between therapeutic and nontherapeutic trials. Clinical trial accruals are not uniform across age, sex, race, place of residence, cancer site, or trial type, underscoring that cancer centers must better understand their source patients to enhance clinical trial participation.