Utility of the JAX Clinical Knowledgebase in capture and assessment of complex genomic cancer data.

Cancer genomic data is continually growing in complexity, necessitating improved methods for data capture and analysis. Tumors often contain multiple therapeutically relevant alterations, and co-occurring alterations may have a different influence on therapeutic response compared to if those alterations were present alone. One clinically important example of this is the existence of a resistance conferring alteration in combination with a therapeutic sensitizing mutation. The JAX Clinical Knowledgebase (JAX-CKB) (https://ckb.jax.org/) has incorporated the concept of the complex molecular profile, which enables association of therapeutic efficacy data with multiple genomic alterations simultaneously. This provides a mechanism for rapid and accurate assessment of complex cancer-related data, potentially aiding in streamlined clinical decision making. Using the JAX-CKB, we demonstrate the utility of associating data with complex profiles comprising ALK fusions with another variant, which have differing impacts on sensitivity to various ALK inhibitors depending on context

Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance.

BACKGROUND: Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. METHODS: In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. RESULTS: We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. CONCLUSIONS: We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response

The Grizzly, April 24, 1987

Professor: One of Eighty Arrested for Protest • Forum Series Ends • Spring Weekend Lacks Enthusiasm • Admissions Expands to New Areas • Letters: Room Selection Process Attacked; Another Attack; Apology; And a Different Response • Students Represent U.C. in D.C. at Center • Chapter Scholars Announced • Notes: Singing Instructions Begin; Student Musician Presents Recital • Final Exam Schedule • Bears Offensive Team Sweeps Haverford Double Header • Crowded House Instruments Variety • Brown Urges Students to Pump on For Fourth Annual Lift-A-Thon • Wood and Lucky Number 13 Gives Runners Record • Tennis Courts Wins • Lady LAX Team Rolling Towards NCAA\u27s • Netters Frustrated in Attempt to Reach End of Season .500 • Athlete of the Week: John Woodhttps://digitalcommons.ursinus.edu/grizzlynews/1188/thumbnail.jp

The Grizzly, May 1, 1987

Will Ursinus Make the Grade? • Commuters Recognized • Student Apathy a Farce • Beatles Now Available on Disc • Dougy is King to Sig Rho • Notes: Summer Tennis Strategies Offered; Continuing Ed. Becomes Assertive; Physical Education Day: May 4th; Band and Jazz Ensemble to Perform • Lacrosse Shoots for 4th Title; Bingaman Breaks Another Record • MAC\u27s Return to Ursinus; Bears Look to Usurp Crown • Golf Ties Record at 15-1: Klee, Ignatowicz Lead Bears to MAC Fifth • Trout Tourney Results • The Men Looking For Glory • Baseball Season Ends on Down Note • Kulp Driven to Excellence • Softball Denied Playoffs • Women Netters .500 • Dolman Leaves with Warm Feelings • Renovations at Myrin • Zucker Retires to Further Musical Interests • Multi-talented Symons Ends Forty Year Career at Ursinus • Page Closes the Book at Ursinushttps://digitalcommons.ursinus.edu/grizzlynews/1189/thumbnail.jp

The Grizzly, April 10, 1987

Pfahler Hall Flooded • L.C.B. Visits a Second Time • Our Town Debuts • Letters: Director of Security at Sheraton Responds to Student Attack on Lorelei; Brothers of AXE Commended; Grizzly Dogged • Skunked Again • Students to Participate in Model UN Conference • Salamanca to Relate Experiences on Terrorism • Bard Graces Ursinus • Notes: UC / St. Joseph\u27s Host MBA Summer Session; Myrin Holds Semi-Annual Book Sale; New Resident Assistants Announced • Athlete of the Week: Kim Wentzel • Santangelo, O\u27Malley Jump Lady Bears to 6-0 Start • Women\u27s Tennis Served Tough Losses • Track\u27s Record: Record Breaking • Ursinus\u27 Champion Lacrosse Team: Vying for Fourth National Title • Opposition Unfavorable to Bears • Golf Team Drives Record to 8-0 • Softball Assumes First Place Position • Room Selection to Start • The Joshua Tree Rates an A • Young Democrats: Exhibiting New Challenges for the Future • Advanced TV Class Produces Ursinus Magazine For Cable Network • Arbor Day Trees Grow Money • Bear Facts: Ursinus Mascot Bearly Knownhttps://digitalcommons.ursinus.edu/grizzlynews/1187/thumbnail.jp

High-resolution deconstruction of evolution induced by chemotherapy treatments in breast cancer xenografts.

The processes by which tumors evolve are essential to the efficacy of treatment, but quantitative understanding of intratumoral dynamics has been limited. Although intratumoral heterogeneity is common, quantification of evolution is difficult from clinical samples because treatment replicates cannot be performed and because matched serial samples are infrequently available. To circumvent these problems we derived and assayed large sets of human triple-negative breast cancer xenografts and cell cultures from two patients, including 86 xenografts from cyclophosphamide, doxorubicin, cisplatin, docetaxel, or vehicle treatment cohorts as well as 45 related cell cultures. We assayed these samples via exome-seq and/or high-resolution droplet digital PCR, allowing us to distinguish complex therapy-induced selection and drift processes among endogenous cancer subclones with cellularity uncertaint

A harmonized meta-knowledgebase of clinical interpretations of somatic genomic variants in cancer

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface () for exploring the harmonized interpretations from these six knowledgebases

Osteoporosis

Objectives Review importance of bone health Define and identify osteopenia and osteoporosis Learn treatment options for osteopenia How to counsel patients How to use FRAX calculator to assist with treatment decisions Learn treatment options for osteoporosis Become familiar with treatment guidelines and option

mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review.

BACKGROUND: The progression of prostate cancer to castration-resistant prostate cancer (CRPC) is often a result of somatic alterations in the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway, suggesting that therapies targeting this pathway might lead to improved survival and efficacy. Here, we systematically evaluate the results of clinical trials investigating mTOR inhibition in CRPC and utilize preclinical data to predict clinical outcomes. METHODS: Trials included in the study were identified through PubMed and via review of conference abstracts cited by relevant review articles. The eligibility of trials was independent of sample size, clinical setting, or date. RESULTS: A total of 14 studies were eligible for qualitative analysis. The clinical setting was variable among studies, and all utilized an allosteric mTOR inhibitor as either a monotherapy or in combination. Molecular criteria were evaluated in three trials. Among most studies, the prostate-specific antigen level declined during treatment, but often increased shortly thereafter. Partial responses to treatment were minimal, and no complete responses were reported. Two studies exploring therapy with an mTOR inhibitor in combination with bicalutamide resulted in minimal efficacy. Overall, allosteric mTOR inhibition was deemed to be inadequate for the treatment of CRPC. CONCLUSION: Preclinical data suggest that a reciprocal feedback mechanism between PI3K and androgen receptor signaling is a potential mechanism behind the clinical inefficacy of mTOR inhibitors in CRPC, indicating combinatorial targeting of PI3K, mTORC1/2, and the androgen receptor might be more effective. Comprehensive analysis of preclinical data to assess clinical trial targets and efficacy may reduce the number of unproductive trials and identify potentially beneficial combinatorial therapies for resistant disease. Target Oncol 2017 Feb; 12(1):47-59