Primary care and community partnerships to promote age-friendly care for Hispanic older adults.

BACKGROUND: Healthcare and community collaborations have the potential to address health-related social needs. We examined the implementation of an educational initiative and collaborative intervention between a geriatric clinic and Area Agency on Aging (AAA) to enhance age-friendly care for a Hispanic patient population. METHODS: As part of a Health Resources and Services Administration (HRSA)-funded Geriatric Workforce Enhancement Program, a geriatric clinic partnered with AAA to embed an English- and Spanish-speaking Social Service Coordinator (SSC). The SSC met with patients during new and annual visits or by referral to address What Matters and Mentation in the patient's primary language, provide education, and make social service referrals. Patients aged 60 and older, who received SSC services during a 12-month period, were defined as the intervention group (n = 112). Using a retrospective chart review, we compared them to a non-intervention group (n = 228) that received primary care. We examined available demographic and clinical data within the age-friendly areas of What Matters and Mentation. Measures included cognitive health screenings, advance care planning, patient education, and community referrals. RESULTS: Most of the intervention groups were eligible for AAA services and had the opportunity for service referrals to address identified needs. A higher proportion of patients within the intervention group completed screenings for cognitive health and advance care planning discussions. CONCLUSION: Interagency partnerships between ambulatory care settings and community-based organizations have the potential to expand access to linguistically and culturally competent age-friendly primary care for older adults.

Lessons Learned from Age-Friendly, Team-Based Training.

According to the Institute of Medicine, immediate steps must be taken across the United States to educate and train the healthcare workforce to work collaboratively to address the needs of the growing older adult population. The Geriatric Practice Leadership Institute (GPLI) was designed to support professional teams working in acute and post-acute care in transforming their organization into a designated Age-Friendly Health System. The program was built around the Institute for Healthcare Improvement's Age-Friendly Health Systems 4Ms framework. This framework focuses on What Matters, Medication, Mentation, and Mobility (the 4Ms) in supporting care for older adults. The GPLI program is an online, seven-month team-based program with four to seven participants from one organization per team. Additionally, each team selected, developed, and completed a quality improvement project based on Age-Friendly Health Systems 4Ms. The curriculum also includes organizational culture, leadership, and interprofessional team-building modules. Using a post-completion survey, the experiences of 41 participants in the GPLI program were assessed. All respondents found the information in the program 'very' or 'extremely' valuable, and their executive sponsor 'very' or 'extremely' valuable in supporting their team's involvement and project. The GPLI program has trained over 200 healthcare professionals and teams that have successfully implemented projects across their organizations.

ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer.

New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). Insulin-like growth factor 1 receptor (IGF-1R) inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways, including phosphatidylinositol-3-kinase-Akt and mitogen-activated protein kinase. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R, and the closely related insulin receptor. Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 < 1 µmol/L. Cell line expression of IGF-1R, IR, IGF-1, IGF-2, IGFBP3, and IGFBP6 did not correlate with sensitivity to OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (P = 0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell-cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared with mock-treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach.

Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer.

A large fraction of non-small cell lung cancers (NSCLC) are dependent on defined oncogenic driver mutations. Although targeted agents exist for EGFR- and EML4-ALK-driven NSCLCs, no therapies target the most frequently found driver mutation, KRAS. Furthermore, acquired resistance to the currently targetable driver mutations is nearly universally observed. Clearly a novel therapeutic approach is needed to target oncogene-driven NSCLCs. We recently showed that the basic helix-loop-helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to Kras-induced senescence. In the current study, we examine the role of TWIST1 in oncogene-driven human NSCLCs. Silencing of TWIST1 in KRAS-mutant human NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or, in some cases, apoptosis. Similar effects were observed in EGFR mutation-driven and c-Met-amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was independent of p53 or p16 mutational status and did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 resulted in significant growth inhibition of KRAS-mutant, EGFR-mutant, and c-Met-amplified NSCLCs. Remarkably, inducible silencing of TWIST1 resulted in significant growth inhibition of established KRAS-mutant tumors. Together these findings suggest that silencing of TWIST1 in oncogene driver-dependent NSCLCs represents a novel and promising therapeutic strategy.

A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer.

BACKGROUND: AT-101 is an oral inhibitor of the antiapoptotic Bcl proteins (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and an inducer of the pro-apoptotic proteins noxa and puma. We studied the efficacy of AT-101 in patients with recurrent chemosensitive extensive-stage small cell lung cancer (SCLC). METHODS: Patients with recurrent "sensitive" SCLC (defined as no progression during and no disease recurrence <2 months after completion of first-line platinum-based chemotherapy) were eligible. AT-101 was administered 20 mg orally daily for 21 of 28 days each cycle for up to six cycles. The primary end point was the objective response rate. RESULTS: At the time of planned interim evaluation, none of the 14 evaluable patients enrolled in the first stage had any response to therapy, and the study was closed permanently for further accrual. Three patients (21%) achieved stable disease after two cycles of therapy. Grade 3 toxicities included anorexia, fatigue, and nausea/vomiting. CONCLUSIONS: AT-101 is not active in patients with recurrent chemosensitive SCLC.

Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer.

UNLABELLED: Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy. SIGNIFICANCE: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.

Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer.

Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models.