Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

Framingham ten-year general cardiovascular disease risk: agreement between BMI-based and cholesterol-based estimates in a South Asian convenience sample.

The goal of this analysis was to determine the agreement between body mass index-based and cholesterol-based ten-year Framingham general cardiovascular disease risk scores among a convenience sample of 773 South Asian Canadian adults attending community-based screening clinics. Scores were calculated using age, systolic blood pressure, antihypertensive use, current smoking, diabetes, and total cholesterol and high density lipoprotein (for cholesterol-based risk) or height and weight (for body mass index-based risk). Mean risk score differences (body mass index-based risk minus cholesterol-based risk) were estimated using paired t-tests. Bland-Altman plots were used to assess agreement between scores. Finally, agreement across risk categories (low [<10%], moderate [10% to <20%], high [> = 20%]) was examined using the kappa statistic. Average agreement between the two risk scores was quite good overall (mean differences of 0.6% for men and 0.5% for women), but increased to about 3% among participants 60-74 years of age. However, Bland-Altman plots revealed that the differences between the two scores and the variability of the differences increased with increasing average 10-year risk. In terms of clinical importance, the limits of agreement were reasonable for women < 60 years (95% confidence interval: -3.2% to 3.1%), but of concern for women 60-74 years (95% confidence interval: -6.0% to 12.3%), men < 60 years (95% confidence interval: -7.1% to 7.3%) and men 6-074 years (95% confidence interval: -13.8% to 18.8%). Agreement across categories was moderate for most sex and age groups examined (kappa values: 0.51 for women < 60 years, 0.50 for women 60-74 years, 0.65 for men < 60 years), except for men 60-74 years, where agreement was only fair (kappa = 0.26). In light of these disagreements, evaluation of a participant's change in cardiovascular disease risk over time will necessitate use of the same risk score (i.e., either body mass index-based or cholesterol-based) at all screening sessions.

Feasibility of community-based screening for cardiovascular disease risk in an ethnic community: the South Asian Cardiovascular Health Assessment and Management Program (SA-CHAMP).

BACKGROUND: South Asian Canadians experience disproportionately high rates of cardiovascular disease (CVD). The goal of this qualitative study was to determine the feasibility of implementing a sustainable, culturally adapted, community-based CVD risk factor screening program for this population. METHODS: South Asians (≥ 45 years) in Calgary, Alberta underwent opportunistic cardiovascular risk factor screening by lay trained volunteers at local religious facilities. Those with elevated blood pressure (BP) or ≥ 1 risk factor underwent point of care cholesterol testing, 10-year CVD risk calculation, counseling, and referral to family physicians and local culturally tailored chronic disease management (CDM) programs. Participants were invited for re-screening and were surveyed about health system follow-up, satisfaction with the program and suggestions for improvement. Changes in risk factors from baseline were estimated using McNemar's test (proportions) and paired t-tests (continuous measures). RESULTS: Baseline assessment was completed for 238 participants (median age 64 years, 51% female). Mean TC, HDL and TC/HDL were 5.41 mmol/L, 1.12 mmol/L and 4.7, respectively. Mean systolic and diastolic blood pressures (mmHg) were 129 and 75 respectively. Blood pressure and TC/HDL ratios exceeded recommended targets in 36% and 58%, respectively, and 76% were at high risk for CVD. Ninety-nine participants (47% female) attended re-screening. 82% had accessed health care providers, 22% reported medication changes and 3.5% had attended the CDM programs. While BP remained unchanged, TC and TC/HDL decreased and HDL increased significantly (mean differences: -0.52 mmol/L, -1.04 and +0.07 mmol/L, respectively). Participants were very satisfied (80%) or satisfied (20%) with the project. Participants suggested screening sessions and CDM programs be more accessible by: delivering evening or weekends programs at more sites, providing transportation, offering multilingual programs/translation assistance, reducing screening wait times and increasing numbers of project staff. CONCLUSIONS: SA-CHAMP demonstrated the feasibility and value of implementing a lay volunteer-led, culturally adapted, sustainable community-based CVD risk factor screening program in South Asian places of worship in Calgary, Alberta, Canada. Subsequent screening and CDM programs were refined based on the learnings from this study. Further research is needed to determine physician and patient factors associated with uptake of and adherence to risk reduction strategies.

Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models.

PURPOSE: Class 1 phosphatidylinositol 3-kinase (PI3K) plays a major role in cell proliferation and survival in a wide variety of human cancers. Here, we investigated biomarker strategies for PI3K pathway inhibitors in non-small-cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Molecular profiling for candidate PI3K predictive biomarkers was conducted on a collection of NSCLC tumor samples. Assays included comparative genomic hybridization, reverse-transcription polymerase chain reaction gene expression, mutation detection for PIK3CA and other oncogenes, PTEN immunohistochemistry, and FISH for PIK3CA copy number. In addition, a panel of NSCLC cell lines characterized for alterations in the PI3K pathway was screened with PI3K and dual PI3K/mTOR inhibitors to assess the preclinical predictive value of candidate biomarkers. RESULTS: PIK3CA amplification was detected in 37% of squamous tumors and 5% of adenocarcinomas, whereas PIK3CA mutations were found in 9% of squamous and 0% of adenocarcinomas. Total loss of PTEN immunostaining was found in 21% of squamous tumors and 4% of adenocarcinomas. Cell lines harboring pathway alterations (receptor tyrosine kinase activation, PI3K mutation or amplification, and PTEN loss) were exquisitely sensitive to the PI3K inhibitor GDC-0941. A dual PI3K/mTOR inhibitor had broader activity across the cell line panel and in tumor xenografts. The combination of GDC-0941 with paclitaxel, erlotinib, or a mitogen-activated protein-extracellular signal-regulated kinase inhibitor had greater effects on cell viability than PI3K inhibition alone. CONCLUSIONS: Candidate biomarkers for PI3K inhibitors have predictive value in preclinical models and show histology-specific alterations in primary tumors, suggesting that distinct biomarker strategies may be required in squamous compared with nonsquamous NSCLC patient populations.

mTOR kinase inhibitor potentiates apoptosis of PI3K and MEK inhibitors in diagnostically defined subpopulations.

The mammalian target of rapamycin (mTOR) is a central node in a complex signaling network that is regulated by several pathways deregulated in human cancers, including the PI3K/Akt and MAPK pathways. Targeting mTOR therefore presents an opportunity for therapeutic intervention. However, mTOR inhibition with rapamycin analogs or kinase inhibitors reduces cell growth but does not induce apoptosis, and the clinical benefit of rapamycin analogs has been modest. In this study we show that mTOR kinase inhibitors can potentiate apoptosis when used in combination with upstream targeted agents such as PI3K and MEK inhibitors. This increased apoptosis is dependent on genetic background, and correlates with active growth factor survival pathways. In PI3K mutant tumors, mTOR inhibition leads to partial reactivation of Akt which allows cells to survive, whereas in KRAS mutant tumors, this same reactivation of Akt occurs but is not required for cell survival. These data suggest the use of selected rational combinations of mTOR kinase inhibitors with other targeted inhibitors in specific tumor genotypes to achieve the maximal cytotoxic response by inhibiting two nodes in the activated signaling network.

GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway.

Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic.

Impact of structured education and self management on rural asthma outcomes.

BACKGROUND: This study trialled the outcome for asthma patients of a brief, nurse led, patient education session with general practice review of an Asthma Action Plan. METHODS: Prospective cohort with before-after measures conducted in six rural general practices. Outcome measures were changes over 12 months in self reported asthma control, quality of life, device use, and unscheduled general practice and emergency department visits for asthma exacerbation. RESULTS: Eighty-three patients participated. Mean asthma control score decreased but did not reach statistical significance (p=0.124). Quality of life improved for adults (Wilcoxon rank signed test for two related samples p<0.001). The proportion of patients who had one or more unscheduled visits to their general practitioner over 12 months decreased from 23% to 13% (p=0.178) and emergency department presentations decreased from 9% to 4% (p=0.102). DISCUSSION: Structured general practice based education appears to be an effective preventive health care program, with the potential to reduce expensive unscheduled use of health services.