Kettering University

About: Kettering University is a education organization based out in Flint, Michigan, United States. It is known for research contribution in the topics: Cancer & RNA. The organization has 6842 authors who have published 7689 publications receiving 337503 citations. The organization is also known as: GMI Engineering & Management Institute & General Motors Institute.

Somatic PIK3CA mutations as a driver of sporadic venous malformations.

Abstract: Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limaye et al., 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.

Frailty as determined by a comprehensive geriatric assessment-derived deficit-accumulation index in older patients with cancer who receive chemotherapy.

Abstract: BACKGROUND Frailty has been suggested as a construct for oncologists to consider in treating older cancer patients. Therefore, the authors assessed the potential of creating a deficit-accumulation frailty index (DAFI) from a largely self-administered comprehensive geriatric assessment (CGA). METHODS Five hundred patients aged ≥65 years underwent a CGA before receiving chemotherapy. A DAFI was constructed, resulting in a 51-item scale, and cutoff values were examined for patients in the robust/nonfrail (cutoff value, 0.0 < 0.2), prefrail (cutoff value, 0.2 < 0.35), and frail (cutoff value, ≥ 0.35) groups. RESULTS Two hundred and fifty patients (50%) were nonfrail, 197 (39%) were prefrail, and 52 (11%) were frail. Older patients (aged ≥ 80 years) and those who had lower education, were living alone, and had higher stage disease were associated with prefrail/frail status. Prefrail/frail patients were more likely to have grade ≥3 toxicity but not to have a dose delay or reduction, and they were more likely to discontinue drug and be hospitalized. The association with grade ≥3 toxicity was attenuated by controlling for a toxicity risk calculator, but the other outcomes were not. CONCLUSIONS A deficit-accumulation frailty index can be constructed from a CGA in older patients with cancer and can indicate the frailty status of the population. The frailty status so determined is associated both with outcomes likely because of chemotherapy toxicity and with those likely because of age-related physiologic and functional deficits and thus can be useful in the overall assessment of the patient. Cancer 2016;122:3865–3872. © 2016 American Cancer Society.

An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer

Abstract: The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.