Hereditary cancer risk assessment and genetic testing in the community urology practice setting.

OBJECTIVES: To evaluate the feasibility of integrating a hereditary cancer risk assessment (HCRA) process in the community urology practice setting for patients with prostate cancer (PCa). METHODS: In this prospective intervention, an HCRA process was implemented across six different community urology clinics between May 2019 and April 2020. The intervention included a process integration during which the workflow at each site was refined, a post-integration period during which HCRA was conducted in all patients with PCa, and a follow-up period during which healthcare providers and patients reported their satisfaction with the HCRA and genetic testing process. RESULTS: Among patients who completed a family history assessment during the post-integration period, 23.6% met guideline criteria for genetic testing. Of all patients seen at the clinic during the post-integration period, 8.7% completed genetic testing; this was a twofold increase over the period immediately preceding process integration (4.2%), and a sevenfold increase over the same period 1 year prior (1.2%). The majority of providers reported that the HCRA was as important as other regularly performed assessments (61.0%) and planned to continue using the process in their practice (68.3%). Most patients believed that the genetic test results were important for their future cancer care (84.7%) and had already shared their test results with at least one family member (63.2%). CONCLUSIONS: This study demonstrated that implementing an HCRA process in the community urology practice setting was feasible, generally favored by providers and patients, and resulted in an increase in the number of patients with PCa who completed genetic testing.

Diagnostic Distinction of Malignant Melanoma and Benign Nevi by a Gene Expression Signature and Correlation to Clinical Outcomes.

Background: Histopathologic examination alone can be inadequate for diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature was clinically validated as an ancillary diagnostic test to differentiate benign nevi from melanoma. The current study assessed the performance of this test in an independent cohort of melanocytic lesions against clinically proven outcomes.Methods: Archival tissue from primary cutaneous melanomas and melanocytic nevi was obtained from four independent institutions and tested with the gene signature. Cases were selected according to pre-defined clinical outcome measures. Malignant lesions were defined as stage I-III primary cutaneous melanomas that produced distant metastases (metastatic to sites other than proximal sentinel lymph node(s)) following diagnosis of the primary lesion. Melanomas that were metastatic at the time of diagnosis, all re-excisions, and lesions with <10% tumor volume were excluded. Benign lesions were defined as cutaneous melanocytic lesions with no adverse long-term events reported.Results: Of 239 submitted samples, 182 met inclusion criteria and produced a valid gene expression result. This included 99 primary cutaneous melanomas with proven distant metastases and 83 melanocytic nevi. Median time to melanoma metastasis was 18 months. Median follow-up time for nevi was 74.9 months. The gene expression score differentiated melanoma from nevi with a sensitivity of 93.8% and a specificity of 96.2%.Conclusions: The results of gene expression testing closely correlate with long-term clinical outcomes of patients with melanocytic neoplasms.Impact: Collectively, this provides strong evidence that the gene signature adds valuable adjunctive information to aid in the accurate diagnosis of melanoma. Cancer Epidemiol Biomarkers Prev; 26(7); 1107-13. ©2017 AACR.

Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma.

PURPOSE: The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes. METHODS: Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer-specific mortality as the primary outcome. RESULTS: In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer-specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14-2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer-specific mortality (HR=1.77; 95% CI, 1.18-2.66; P=0.006). Five-year lung cancer-specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer-specific survival (P<0.001 and 0.015, respectively), compared with low mPS. CONCLUSION: This study validates CCP score and mPS as independent prognostic markers for lung cancer-specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone.

Impact of the Cell Cycle Progression Test on Physician and Patient Treatment Selection for Localized Prostate Cancer.

PURPOSE: The cell cycle progression test is a validated molecular assay that assesses prostate cancer specific disease progression and mortality risk when combined with clinicopathological parameters. We present the results from PROCEDE-1000, a large, prospective registry designed to evaluate the impact of the cell cycle progression test on shared treatment decision making for patients newly diagnosed with prostate cancer. MATERIALS AND METHODS: Untreated patients with newly diagnosed prostate adenocarcinoma were enrolled in the study and the cell cycle progression test was performed on the initial prostate biopsy tissue. A set of 4 sequential surveys tracked changes relative to initial therapy recommendations (before cell cycle progression) based on clinicopathological parameters following physician review of the cell cycle progression test result, physician/patient review of the cell cycle progression test results and a minimum of 3 months of clinical followup (actual treatment). RESULTS: Of the 1,596 patients enrolled in this registry 1,206 were eligible for analysis. There was a significant reduction in the treatment burden recorded at each successive evaluation (p <0.0001), with the mean number of treatments per patient decreasing from 1.72 before the cell cycle progression test to 1.16 in actual followup. The cell cycle progression test caused a change in actual treatment in 47.8% of patients. Of these changes 72.1% were reductions and 26.9% were increases in treatment. For each clinical risk category there was a significant change in treatment modality (intervention vs nonintervention) before vs after cell cycle progression testing (p=0.0002). CONCLUSIONS: The cell cycle progression test has a significant impact in assisting physicians and patients reach personalized treatment decisions.

Characterization of the cellular and antitumor effects of MPI-0479605, a small-molecule inhibitor of the mitotic kinase Mps1.

Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics.

Chemical proteomics identifies Nampt as the target of CB30865, an orphan cytotoxic compound.

Drug discovery based on cellular phenotypes is impeded by the challenge of identifying the molecular target. To alleviate this problem, we developed a chemical proteomic process to identify cellular proteins that bind to small molecules. CB30865 is a potent (subnanomolar) and selective cytotoxic compound of previously unknown mechanism of action. By combining chemical proteomics with biochemical and cellular pharmacology we have determined that CB30865 cytotoxicity is due to subnanomolar inhibition of nicotinamide phosphoribosyltransferase (Nampt), an enzyme present in the NAD biosynthetic pathway. Cancer cells develop dependence on Nampt due to increased energy requirements and the elevated activity of NAD consuming enzymes such as sirtuins and mono and poly(ADP-ribose) polymerases (PARPs). These findings suggest new chemical starting points for Nampt inhibitors and further implicate this enzyme as a target in cancer.

2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97).

Valosin-containing protein (VCP; also known as p97) is a member of the AAA ATPase family with a central role in the ubiquitin-degradation of misfolded proteins. VCP also exhibits antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. We have discovered that 2-anilino-4-aryl-1,3-thiazoles are potent drug-like inhibitors of this enzyme. The identified compounds show low nanomolar VCP potency, demonstrate SAR trends, and show activity in a mechanism based cellular assay. This series of compounds represents the first steps towards a novel, small molecule VCP inhibitor as a cancer therapeutic.

The protein network of HIV budding.

HIV release requires TSG101, a cellular factor that sorts proteins into vesicles that bud into multivesicular bodies (MVB). To test whether other proteins involved in MVB biogenesis (the class E proteins) also participate in HIV release, we identified 22 candidate human class E proteins. These proteins were connected into a coherent network by 43 different protein-protein interactions, with AIP1 playing a key role in linking complexes that act early (TSG101/ESCRT-I) and late (CHMP4/ESCRT-III) in the pathway. AIP1 also binds the HIV-1 p6(Gag) and EIAV p9(Gag) proteins, indicating that it can function directly in virus budding. Human class E proteins were found in HIV-1 particles, and dominant-negative mutants of late-acting human class E proteins arrested HIV-1 budding through plasmal and endosomal membranes. These studies define a protein network required for human MVB biogenesis and indicate that the entire network participates in the release of HIV and probably many other viruses.