Phillip J. Gray

Extracellular Heat Shock Proteins in Cell Signaling and Immunity

Abstract:  Extracellular stress proteins including heat shock proteins (Hsps) and glucose‐regulated proteins (Grps) are emerging as important mediators of intercellular signaling and transport. Release of such proteins from cells is triggered by physical trauma and behavioral stress as well as exposure to immunological “danger signals.” Stress protein release occurs both through physiological secretion mechanisms and during cell death by necrosis. After release into the extracellular fluid, Hsp or Grp may then bind to the surfaces of adjacent cells and initiate signal transduction cascades as well as the transport of cargo molecules, such as antigenic peptides. In addition, Hsp60 and Hsp70 are able to enter the bloodstream and may possess the ability to act at distant sites in the body. Many of the effects of extracellular stress proteins are mediated through cell‐surface receptors. Such receptors include toll‐ like receptors (TLRs) 2 and 4, CD40, CD91, CCR5, and members of the scavenger receptor family, such as LOX‐1 and SREC‐1. The possession of a wide range of receptors for the Hsp and Grp family permits binding to a diverse range of cells and the performance of complex multicellular functions particularly in immune cells and neurons.

Use of Potentially Curative Therapies for Muscle-invasive Bladder Cancer in the United States: Results from the National Cancer Data Base

BACKGROUND Despite its lethal potential, many patients with muscle-invasive bladder cancer (MIBC) do not receive aggressive, potentially curative therapy consistent with established practice standards. OBJECTIVE To characterize the treatments received by patients with MIBC and analyze their use according to sociodemographic, clinical, pathologic, and facility measures. DESIGN, SETTING, AND PARTICIPANTS Using the National Cancer Data Base, we analyzed 28 691 patients with MIBC (stages II-IV) treated between 2004 and 2008, excluding those with cT4b tumors or distant metastases. Treatments included radical or partial cystectomy with or without chemotherapy (CT), chemoradiotherapy (CRT), radiation therapy (RT), or CT alone and observation following biopsy. Aggressive therapy (AT) was defined as radical or partial cystectomy or definitive RT/CRT (total dose ≥ 50 Gy). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS AT use and correlating variables were assessed by multivariable, generalized estimating equation models adjusted for facility clustering. RESULTS AND LIMITATIONS According to the database, 52.5% of patients received AT; 44.9% were treated surgically, 7.6% received definitive CRT or RT, and 25.9% of patients received observation only. AT use decreased with advancing age (odds ratio [OR]: 0.34 for age 81-90 yr vs ≤ 50 yr; p<0.001). AT use was also lower in racial minorities (OR: 0.74 for black race; p<0.001), the uninsured (OR: 0.73; p<0.001), Medicaid-insured patients (OR: 0.81; p=0.01), and at low-volume centers (OR: 0.64 vs high-volume centers; p<0.001). Use of AT was higher with increasing tumor stage (OR: 2.23 for T3/T4a vs T2; p<0.001) and nonurothelial histology (OR: 1.25 and 1.43 for squamous and adenocarcinoma, respectively; p<0.001). Study limitations include retrospective design and lack of information about patient and provider motivations regarding therapy selection. CONCLUSIONS AT for MIBC appears underused, especially in the elderly and in groups with poor socioeconomic status. These data point to a significant unmet need to inform policy makers, payers, and physicians regarding appropriate therapies for MIBC.

Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1

Heat shock factor 1 (HSF1), the transcriptional activator of the heat shock genes, is increasingly implicated in cancer. We have shown that HSF1 binds to the corepressor metastasis-associated protein 1 (MTA1) in vitro and in human breast carcinoma samples. HSF1–MTA1 complex formation was strongly induced by the transforming ligand heregulin and complexes incorporated a number of additional proteins including histone deacetylases (HDAC1 and 2) and Mi2α, all components of the NuRD corepressor complex. These complexes were induced to assemble on the chromatin of MCF7 breast carcinoma cells and associated with the promoters of estrogen-responsive genes. Such HSF1 complexes participate in repression of estrogen-dependent transcription in breast carcinoma cells treated with heregulin and this effect was inhibited by MTA1 knockdown. Repression of estrogen-dependent transcription may contribute to the role of HSF1 in cancer.

Targeting the oncogene and kinome chaperone CDC37

CDC37 is a molecular chaperone that physically stabilizes the catalytic domains found in protein kinases and is therefore a wide-spectrum regulator of protein phosphorylation. It is also an overexpressed oncoprotein that mediates carcinogenesis by stabilizing the compromised structures of mutant and/or overexpressed oncogenic kinases. Recent work shows that such dependency of malignant cells on increased CDC37 expression is a vulnerability that can be targeted in cancer by agents that deplete or inhibit CDC37. CDC37 is thus a candidate for broad-spectrum molecular cancer therapy.

Patient‐reported outcomes after 3‐dimensional conformal, intensity‐modulated, or proton beam radiotherapy for localized prostate cancer

Recent studies have suggested differing toxicity patterns for patients with prostate cancer who receive treatment with 3‐dimensional conformal radiotherapy (3DCRT), intensity‐modulated radiotherapy (IMRT), or proton beam therapy (PBT).

Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Members of the 90-kDa heat shock protein (HSP90) family are known to bind and stabilize intermediates in a wide variety of cell signaling pathways and contribute to their dysregulation in cancer. An important intracellular cofactor for HSP90 is Cdc37, a protein with a broad role in fostering the activities of protein kinases. By targeting Cdc37 using RNA interference, we have shown that the loss of Cdc37 function induces irreversible growth arrest in androgen receptor-positive and -negative prostate carcinoma cells. In contrast to HSP90-directed agents, Cdc37 targeting seems to affect cancer cells through a distinct mechanism and does not significantly deplete the intracellular levels of most known HSP90 client proteins. Instead, Cdc37 depletion inhibits cellular kinase activity and flux through growth-promoting signal transduction cascades. We show that the loss of Cdc37 leads to reduced activity of the Erk, Akt, mTOR, and androgen-induced pathways. We have also discovered synergistic interactions between Cdc37 inactivation and the HSP90-inhibitory anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17AAG). These interactions involve enhanced degradation of proteins essential for growth and inhibition of 17AAG-induced expression of the antiapoptotic HSP70. Thus, Cdc37 is essential for maintaining prostate tumor cell growth and may represent a novel target in the search for multitargeted therapies based on the HSP90 chaperone system.

Declining Use of Radiotherapy for Adverse Features After Radical Prostatectomy: Results From the National Cancer Data Base

BACKGROUND Patterns of postoperative radiotherapy (RT) use in prostate cancer (PCa) after the publication of major randomized trials have not been well characterized. OBJECTIVE To describe patterns of postoperative RT use after radical prostatectomy (RP) in patients with adverse pathologic features in the United States. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of 97 270 patients with PCa diagnosed between 2005 and 2011 whose presentation and outcomes were recorded in the National Cancer Data Base. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Temporal changes in receipt of postoperative RT and factors associated with receipt of this treatment using the Cochran-Armitage trend test and multiple logistic regression, respectively. RESULTS AND LIMITATIONS Between 2005 and 2011, receipt of postoperative RT decreased steadily from 9.1% to 7.3% (ptrend<0.001). Use of RT with or without androgen deprivation therapy monotonically decreased with advancing age from 8.5% in patients aged 18-59 yr to 6.8% in patients aged 70-79 yr (ptrend<0.001). Receipt of RT was higher at community cancer programs compared with teaching/research centers (14% vs 7.3%; odds ratio [OR]: 2.16; p<0.001), in those with pT3-4 disease and positive margins compared with those with pT3-4 and negative margins (17% vs 5.9%; OR: 2.89; p<0.001), and in patients with a Gleason score of 8-10 compared with those with a Gleason score of 2-6 (17% vs 4.2%; OR: 3.50; p<0.001). Limitations include lack of postprostatectomy prostate-specific antigen level. CONCLUSIONS Postoperative RT use for localized PCa in patients with adverse pathologic features is declining in the United States. PATIENT SUMMARY In this report, we show that use of postoperative radiotherapy in patients with prostate cancer with adverse pathologic features is declining. Patients treated at community cancer programs, those with locally advanced disease and positive margins, and those with a high Gleason score were more likely to receive postoperative radiotherapy.

Androgen Deprivation With or Without Radiation Therapy for Clinically Node-Positive Prostate Cancer

BACKGROUND Clinically lymph node-positive (cN+) prostate cancer (PCa) is an often-fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base. METHODS Patients with cN+ PCa and without distant metastases diagnosed between 2004 and 2011 were included. Five-year overall survival for patients diagnosed between 2004 and 2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics, and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality. RESULTS Of 3540 total patients, 32.2% were treated with ADT alone and 51.4% received ADT+RT. Compared with ADT alone, patients treated with ADT+RT were younger and more likely to have private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values. After PS matching, 318 patients remained in each group. Compared with ADT alone, ADT+RT was associated with a 50% decreased risk of five-year all-cause mortality (HR = 0.50, 95% CI = 0.37 to 0.67, two-sided P < .001; crude OS rate: 71.5% vs 53.2%). CONCLUSIONS Using a large national database, we have identified a statistically significant survival benefit for patients with cN+ PCa treated with ADT+RT. These data, if appropriately validated by randomized trials, suggest that a substantial proportion of such patients at high risk for prostate cancer death may be undertreated, warranting a reevaluation of current practice guidelines.

Clinical–Pathologic Stage Discrepancy in Bladder Cancer Patients Treated With Radical Cystectomy: Results From the National Cancer Data Base

PURPOSE To examine the accuracy of clinical staging and its effects on outcome in bladder cancer (BC) patients treated with radical cystectomy (RC), using a large national database. METHODS AND MATERIALS A total of 16,953 patients with BC without distant metastases treated with RC from 1998 to 2009 were analyzed. Factors associated with clinical-pathologic stage discrepancy were assessed by multivariate generalized estimating equation models. Survival analysis was conducted for patients treated between 1998 and 2004 (n=7270) using the Kaplan-Meier method and Cox proportional hazards models. RESULTS At RC 41.9% of patients were upstaged, whereas 5.9% were downstaged. Upstaging was more common in females, the elderly, and in patients who underwent a more extensive lymphadenectomy. Downstaging was less common in patients treated at community centers, in the elderly, and in Hispanics. Receipt of preoperative chemotherapy was highly associated with downstaging. Five-year overall survival rates for patients with clinical stages 0, I, II, III, and IV were 67.2%, 62.9%, 50.4%, 36.9%, and 27.2%, respectively, whereas those for the same pathologic stages were 70.8%, 75.8%, 63.7%, 41.5%, and 24.7%, respectively. On multivariate analysis, upstaging was associated with increased 5-year mortality (hazard ratio [HR] 1.80, P<.001), but downstaging was not associated with survival (HR 0.88, P=.160). In contrast, more extensive lymphadenectomy was associated with decreased 5-year mortality (HR 0.76 for ≥10 lymph nodes examined, P<.001), as was treatment at an National Cancer Institute-designated cancer center (HR 0.90, P=.042). CONCLUSIONS Clinical-pathologic stage discrepancy in BC patients is remarkably common across the United States. These findings should be considered when selecting patients for preoperative or nonoperative management strategies and when comparing the outcomes of bladder sparing approaches to RC.

Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival.

OBJECTIVES Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain-only oligometastases (SBO) is not well defined. We sought to analyze the effect of differing therapeutic paradigms in this subpopulation. MATERIALS AND METHODS We retrospectively analyzed NSCLC patients with 1-4 SBO diagnosed between 1/2000 and 1/2011 at our institution. Patients with T0 tumors or documented Karnofsky Performance Status <70 were excluded. Aggressive thoracic therapy (ATT) was defined as resection of the primary disease or chemoradiotherapy whose total radiation dose exceeded 45 Gy. Cox proportional hazards and competing risks models were used to analyze factors affecting survival and first recurrence in the brain. RESULTS Sixty-six patients were included. Median follow-up was 31.9 months. Intrathoracic disease extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients received ATT, 28 did not. Patients receiving ATT were younger (median age 55 vs. 60.5 years, p=0.027) but were otherwise similar to those who did not. Receipt of ATT was associated with prolonged median overall survival (OS) (26.4 vs. 10.5 months; p<0.001) with actuarial 2-year rates of 54% vs. 26%. ATT remained associated with OS after controlling for age, thoracic stage, performance status and initial brain therapy (HR 0.40, p=0.009). On multivariate analysis, the risk of first failure in the brain was associated with receipt of ATT (HR 3.62, p=0.032) and initial combined modality brain therapy (HR 0.34, p=0.046). CONCLUSION Aggressive management of thoracic disease in NSCLC patients with SBO is associated with improved survival. Careful management of brain disease remains important, especially for those treated aggressively.