A roadmap to establishing global oncology as a priority initiative within a National Cancer Institute-designated cancer center.

As the burden of cancers impacting low- and middle-income countries is projected to increase, formation of strategic partnerships between institutions in high-income countries and low- and middle-income country institutions may serve to accelerate cancer research, clinical care, and training. As the US National Cancer Institute and its Center for Global Health continue to encourage cancer centers to join its global mission, academic cancer centers in the United States have increased their global activities. In 2015, the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, responded to the call for international partnership in addressing the global cancer burden through the establishment of the Global Cancer Program as a priority initiative. In developing the Global Cancer Program, we galvanized institutional support to foster sustained, bidirectional, equitable, international partnerships in global cancer control. Our focus and intent in disseminating this commentary is to share experiences and lessons learned from the perspective of a US-based, National Cancer Institute-designated cancer center and to provide a roadmap for other high-income institutions seeking to strategically broaden their missions and address the complex challenges of global cancer control. Herein, we review the formative evaluation, governance, strategic planning, investments in career development, funding sources, program evaluation, and lessons learned. Reflecting on the evolution of our program during the first 5 years, we observed in our partners a powerful shift toward a locally driven priority setting, reduced dependency, and an increased commitment to research as a path to improve cancer outcomes in resource-constrained settings.

Cancer Research in 2030: A unique strategic planning process at a comprehensive cancer center.

Following the successful renewal of its Cancer Center Support Grant (CCSG), leadership of the UCSF Helen Diller Comprehensive Cancer Center (HDFCCC) began a strategic planning process. The motivation was to think about where cancer research was going in the future; and with this vision to define a general scientific direction, mission, and priorities. HDFCCC Leadership began discussions about a new strategic plan in early 2018. From these meetings, the theme of "Cancer Research in 2030" arose: that is, what will cancer research look like in 2030? This forward-looking focus was intended to encourage creativity unconfined by a particular institutional structure or grant mechanism. Focusing on the science paved the way for an innovative, actionable, and motivating strategic planning process. Here, we describe the three-phase process, and the various groups involved across the HDFCCC and UCSF. We present the unique framework based on a cells-to-society model and an individual experience perspective, which led to the development of a logic model and ongoing implementation of tactics and tracking progress. We believe that sharing this process and its results will be of value to cancer centers and cancer researchers across the network of NCI comprehensive cancer centers, and cancer research centers in general.

From Cancer Epidemiology to Policy and Practice: the Role of a Comprehensive Cancer Center.

Purpose of Review: Cancer incidence and mortality are decreasing, but inequities in outcomes persist. This paper describes the San Francisco Cancer Initiative (SF CAN) as a model for the systematic application of epidemiological evidence to reduce the cancer burden and associated inequities. Recent Findings: SF CAN is a multi-institutional implementation of existing evidence on the prevention and early detection of five common cancers (i.e., breast, prostate, colorectal, liver, and lung/tobacco-related cancers) accounting for 50% of cancer deaths in San Francisco. Five Task Forces follow individual logic models designating inputs, outputs, and outcomes. We describe the progress made and the challenges faced by each Task Force after 5 years of activity. Summary: SF CAN is a model for how the nation's Comprehensive Cancer Centers are ideally positioned to leverage cancer epidemiology for evidence-based initiatives that, along with genuine community engagement and multiple stakeholders, can reduce the population burden of cancer.

Validation of Anticorrelated TGFß Signaling and Alternative End-Joining DNA Repair Signatures that Predict Response to Genotoxic Cancer Therapy.

PURPOSE: Loss of TGFß signaling increases error-prone alternative end-joining (alt-EJ) DNA repair. We previously translated this mechanistic relationship as TGFß and alt-EJ gene expression signatures, which we showed are anticorrelated across cancer types. A score representing anticorrelation, ßAlt, predicts patient outcome in response to genotoxic therapy. Here we sought to verify this biology in live specimens and additional datasets. EXPERIMENTAL DESIGN: Human head and neck squamous carcinoma (HNSC) explants were treated in vitro to test whether the signatures report TGFß signaling, indicated by SMAD2 phosphorylation, and unrepaired DNA damage, indicated by persistent 53BP1 foci after irradiation or olaparib. A custom NanoString assay was implemented to analyze the signatures' expression in explants. Each signature gene was then weighted by its association with functional responses to define a modified score, ßAltw, that was retested for association with response to genotoxic therapies in independent datasets. RESULTS: Most genes in each signature were positively correlated with the expected biological response in tumor explants. Anticorrelation of TGFß and alt-EJ signatures measured by NanoString was confirmed in explants. ßAltw was significantly (P < 0.001) better than ßAlt in predicting overall survival in response to genotoxic therapy in The Cancer Genome Atlas (TCGA) pancancer patients and in independent HNSC and ovarian cancer patient datasets. CONCLUSIONS: Association of the TGFß and alt-EJ signatures with their biological response validates TGFß competency as a key mediator of DNA repair that can be readily assayed by gene expression. The predictive value of ßAltw supports its development to assist in clinical decision making.

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1-S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.

Type of anesthesia and postoperative delirium after vascular surgery.

OBJECTIVE: The purpose of this study was to investigate the association between general (GA), regional (RA), and local (LA) anesthetic techniques with respect to the development of delirium after vascular surgery. The authors hypothesized that patients undergoing GA for vascular surgery would have a higher incidence of postoperative delirium. The role of LA with respect to postoperative delirium in vascular surgery patients previously has not been reported. DESIGN: Retrospective review. SETTING: Tertiary referral center, university hospital. PARTICIPANTS: 500 patients undergoing vascular surgical procedures. INTERVENTIONS: Based on the chosen anesthetic technique, all patients were divided into GA, RA, and LA groups, respectively. Exclusion criteria were patients with preoperative dementia or abnormal level of consciousness, patients undergoing open abdominal aneurysm repair surgery, and patients undergoing carotid endarterectomy. All anesthetic techniques were conducted according to routine institutional practices. Patients in both the RA and LA groups received intravenous sedation. MEASUREMENTS AND MAIN RESULTS: Three hundred ninety-six (79%) patients received GA, 73 (15%) RA, and 31 (6%) LA. The overall incidence of delirium was 19.4% and rates were similar among the 3 groups, with 73 (18.4%) patients in the GA group, 17 (23.2%) in the RA group, and 7 (22.5%) in the LA group (p = 0.56). Patients in the LA group were more likely to have emergency surgery and also had a higher incidence of previous cerebrovascular accidents or transient ischemic attacks. There was no significant difference with respect to either onset or duration of delirium among the 3 groups. Median length of hospital stay and in-hospital mortality were similar among the 3 groups. CONCLUSIONS: Delirium rates after vascular surgery were similar with local, regional, or general anesthesia techniques. The presence of risk factors for the development of postoperative delirium should not influence the type of anesthesia provided.

Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib.

Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in DNA repair. PARP inhibitors can act as chemosensitizers, or operate on the principle of synthetic lethality when used as single agent. Clinical trials have shown drugs in this class to be promising for BRCA mutation carriers. We postulated that inability to demonstrate response in non-BRCA carriers in which BRCA is inactivated by other mechanisms or with deficiency in homologous recombination for DNA repair is due to lack of molecular markers that define a responding subpopulation. We identified candidate markers for this purpose for olaparib (AstraZeneca) by measuring inhibitory effects of nine concentrations of olaparib in 22 breast cancer cell lines and identifying features in transcriptional and genome copy number profiles that were significantly correlated with response. We emphasized in this discovery process genes involved in DNA repair. We found that the cell lines that were sensitive to olaparib had a significant lower copy number of BRCA1 compared to the resistant cell lines (p value 0.012). In addition, we discovered seven genes from DNA repair pathways whose transcriptional levels were associated with response. These included five genes (BRCA1, MRE11A, NBS1, TDG, and XPA) whose transcript levels were associated with resistance and two genes (CHEK2 and MK2) whose transcript levels were associated with sensitivity. We developed an algorithm to predict response using the seven-gene transcription levels and applied it to 1,846 invasive breast cancer samples from 8 U133A/plus 2 (Affymetrix) data sets and found that 8-21 % of patients would be predicted to be responsive to olaparib. A similar response frequency was predicted in 536 samples analyzed on an Agilent platform. Importantly, tumors predicted to respond were enriched in basal subtype tumors. Our studies support clinical evaluation of the utility of our seven-gene signature as a predictor of response to olaparib.

Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice.

OBJECTIVE: AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase ß (CaMKKß) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS: Mice lacking either Camkkß or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS: Deletion of Camkkß in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS: Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.

PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study.

PPM1D (protein phosphatase magnesium-dependent 1δ) maps to the 17q23.2 amplicon and is amplified in ∼8% of breast cancers. The PPM1D gene encodes a serine threonine phosphatase, which is involved in the regulation of several tumour suppressor pathways, including the p53 pathway. Along with others, we have recently shown that PPM1D is one of the drivers of the 17q23.2 amplicon and a promising therapeutic target. Here we investigate whether PPM1D is overexpressed when amplified in breast cancers and the correlations between PPM1D overexpression and amplification with clinicopathological features and survival of breast cancer patients from a cohort of 245 patients with invasive breast cancer treated with therapeutic surgery followed by adjuvant anthracycline-based chemotherapy. mRNA was extracted from representative sections of tumours containing >50% of tumour cells and subjected to TaqMan quantitative real-time PCR using primers for PPM1D and for two housekeeping genes. PPM1D overexpression was defined as the top quartile of expression levels. Chromogenic in situ hybridization with in-house-generated probes for PPM1D was performed. Amplification was defined as >50% of cancer cells with >5 signals per nucleus/large gene clusters. PPM1D overexpression and amplification were found in 25 and 6% of breast cancers, respectively. All cases harbouring PPM1D amplification displayed PPM1D overexpression. PPM1D overexpression was inversely correlated with expression of TOP2A, EGFR and cytokeratins 5/6 and 17. PPM1D amplification was significantly associated with HER2 overexpression, and HER2, TOP2A and CCND1 amplification. No association between PPM1D gene amplification and PPM1D mRNA overexpression with survival was observed. In conclusion, PPM1D is consistently overexpressed when amplified; however, PPM1D overexpression is more pervasive than gene amplification. PPM1D overexpression and amplification are associated with tumours displaying luminal or HER2 phenotypes. Co-amplification of PPM1D and HER2/TOP2A and CCND1 are not random events and may suggest the presence of a 'firestorm' genetic profile.

Mismatch repair deficient colorectal cancer in the era of personalized treatment.

The molecular and genetic subtyping of cancer has allowed the emergence of individualized therapies. This approach could potentially deliver treatments that have both increased efficacy as well as reduced toxicity. A well-defined subtype of colorectal cancer (CRC) is characterized by a deficiency in the mismatch repair (MMR) pathway. MMR deficiency not only contributes to the pathogenesis of a large proportion of CRC, but also determines the response to many of the drugs that are frequently used to treat this disease. In this Review we describe the MMR deficient phenotype and discuss how a deficiency in this DNA repair process may impact on the management of CRC, including surgery, adjuvant chemotherapy and the choice of systemic agents for the palliation of advanced disease. We also discuss how the DNA repair defect in MMR deficient CRC could be exploited in the development of novel therapeutic strategies.