Prostatic Neoplasms: Hudes GR

Montie JE, Clark PE, Eisenberger MA, El-Galley R, Greenberg RE, Herr HW, Hudes GR, Kuban DA, Kuzel TM, Lange PH, Lele SM, Michalski J, Patterson A, Pohar KS, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00046. · University of Michigan Comprehensive Cancer Center. · J Natl Compr Canc Netw. · Pubmed #19176203 No free full text.

This publication has no abstract.

Montie JE, Abrahams NA, Bahnson RR, Eisenberger MA, El-Galley R, Herr HW, Hudes GR, Kuzel TM, Lange PH, Patterson A, Pollack A, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00097. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17112448 No free full text.

This publication has no abstract.

David AK, Khwaja R, Hudes GR. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. · Drugs Aging. · Pubmed #12831292 No free full text.

Abstract: Prostate cancer is a heterogeneous disease characterised by a long natural history relative to other solid tumours. With the diagnosis of prostate cancer being made earlier, the emphasis of treatment has shifted from palliation of symptoms to altering disease-related morbidity and mortality and thus improving overall survival. Treatment of prostate cancer increasingly involves an approach that combines local therapies directed at the primary tumour together with systemic therapies to potentiate their effect and to control subclinical metastatic disease. Patients with localised tumours who are at high risk of relapsing with radiation therapy alone are surviving longer because of the addition of adjuvant hormonal therapy. Although a survival benefit in similar patients undergoing prostatectomy has not yet been established, preliminary results indicate that adjuvant hormonal therapy delays relapse. Chemotherapy is an effective palliative modality for patients with hormone- refractory metastatic disease, and recently completed phase III trials will determine if chemotherapy can prolong survival for this group. The role of chemotherapy in patients with locally advanced tumours is also being investigated in randomised clinical trials. Because bone is the dominant site of metastases for most patients with prostate cancer, the development of therapies that can slow tumour growth specifically within bone is a logical strategy. Bisphosphonates and bone-targeted radionuclides are two such approaches that have shown encouraging results even in the most advanced stages of the disease. Although one can now reasonably hypothesise that survival has improved because of recent therapeutic advances, it remains to be conclusively established that cytotoxic or other systemic therapy can extend survival of patients with prostate cancer. Only the results of ongoing randomised trials can definitely establish that more patients with locally advanced and metastatic prostate cancer are living longer.

Hudes GR. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. · Invest New Drugs. · Pubmed #12099576 No free full text.

Abstract: Inhibiting androgen receptor (AR) activation through medical or surgical castration and blockade of AR-androgen binding is the cornerstone of treatment for advanced prostate cancer. However, in most cases tumor growth eventually becomes androgen independent. Alternative mechanisms of AR activation, some of which involve growth factor receptor signaling, have been demonstrated in prostate cancer models, and it is likely that a number of autocrine and paracrine growth factor ligand-receptor interactions such as those of epidermal growth factors, fibroblast growth factors, and insulin-like growth factors contribute to the androgen independent phenotype by promoting cell proliferation and survival. Blocking activation and signaling through growth factor receptors and upstream signaling proteins has emerged as a credible approach to cancer treatment. Successful application of this approach in prostate cancer using a growing array of small molecule kinase inhibitors, antibodies, and antisense oligonucleotides will be greatly accelerated by elucidation of the key signaling pathways that maintain the androgen independent phenotype.

Obasaju C, Hudes GR. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. · Hematol Oncol Clin North Am. · Pubmed #11525295 No free full text.

Abstract: Although their ultimate value in prostate cancer therapy remains to be defined in randomized trials, docetaxel and paclitaxel are active agents in HRPC. Combination therapies using either of these taxanes plus oral EMP show reproducible antitumor activity that appears to be greater and more durable than that of single-agent treatment. Although the optimal combination and schedule have not been determined, weekly paclitaxel and EMP and docetaxel given every 3 weeks or by weekly infusion with EMP are useful treatment options for patients with progressive HRPC. The gastrointestinal toxicity of EMP has been reduced by intermittent rather than continuous administration, and other toxicities may be reduced further by use of intravenous EMP. Although there has been progress, the median time to progression of 5 to 6 months for current taxane-based therapies suggests that they will not have major impact on overall survival for patients with HRPC. Greater benefit may be possible earlier in the course of prostate cancer, and the activity of the taxane-EMP combinations is sufficient to justify clinical trials of adjuvant or neoadjuvant chemotherapy for selected groups of patients with locally advanced and poor-prognosis tumors. Armed with many new molecularly targeted agents that may interact favorably with taxanes, it should be possible to build on current antimicrotubule regimens to improve activity in HRPC. Taxane-EMP combinations provide a platform on which to test additional agents that may enhance the apoptotic response or circumvent cellular stress adaptations that confer drug resistance. Further elucidation of signaling pathways that regulate microtubule dynamics and programmed cell death after exposure to microtubule inhibitors would provide a more rational guide for integrating specific inhibitors of signal transduction with current taxane-based therapies. Pharmacokinetic and pharmacodynamic studies will play a key role in the development of future taxane-based therapies for prostate cancer.

Obasaju C, Manola J, Hudes GR, Khandekar JD, Citrin DL, Carbone P, Trump DL. · Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. · Am J Clin Oncol. · Pubmed #11319290 No free full text.

Abstract: Menogaril is a semisynthetic anthracycline that is less cardiotoxic than doxorubicin in a preclinical model. We conducted a phase II trial to determine the activity of menogaril in hormone-refractory prostate cancer. Between October 1985 and November 1987, 32 eligible patients were enrolled and were divided into good- and poor-risk categories, the latter being defined by prior radiotherapy to less than one third of the marrow-containing skeleton. Good-risk patients received a starting dose of 200 mg/m2 by 60-minute IV infusion, whereas the poor-risk patients received 160 mg/m2. Treatment was repeated every 3 weeks until disease progression. Menogaril caused leukopenia in 90% of patients, of whom 47% had grade III or IV toxicity. Thrombocytopenia was uncommon and mild, with only three patients (9%) experiencing grade II toxicity. Nonhematologic toxicity included mucositis (9%), and mild weight loss in 33% of patients. Nine patients (28%) had stable disease of 3 or more months' duration. There were no objective partial or complete responses. The median time to progression for the entire group was 10 weeks, and the median survival time for all patients was 24 weeks. Because of appreciable toxicity and limited antitumor activity, further study of menogaril cannot be recommended in hormone-refractory prostate cancer.

McDermott RS, Anderson PR, Greenberg RE, Milestone BN, Hudes GR. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. · Cancer. · Pubmed #15468187 links to  free full text

Abstract: BACKGROUND: Cranial nerve lesions due to metastases from prostate carcinoma to the skull base are an uncommon yet clinically significant finding. METHODS: The authors report the clinical features, treatment, and outcomes for 15 patients who presented with cranial nerve palsies complicating metastatic prostate carcinoma. Patient charts identified from a Fox Chase Cancer Center treatment data base were reviewed. RESULTS: All patients had hormone-refractory disease at the time of symptom onset. Twelve of 15 patients had received prior chemotherapy, and 13 of 15 patients had received prior radiation therapy to areas of bony pain. Symptoms varied from recognized clinical syndromes involving multiple cranial nerves to isolated cranial nerve lesions. All patients had lesions at the skull base that were visualized on computed tomography scans or magnetic resonance images. All patients were treated with palliative radiation therapy to either the whole brain or the skull base. Fourteen of 15 patients had a clinical (either partial or complete) response to radiation therapy. All responding patients subsequently died of prostate carcinoma without worsening of residual or development of new cranial nerve symptoms. Ten of 15 patients (67%) died within 3 months of developing symptoms, and the remaining 5 patients lived between 9 months and 31 months from onset of symptoms. CONCLUSIONS: The authors concluded that palliative radiation therapy should be considered in this heterogeneous group of patients given the potential for significant symptom improvement.

Ranganathan S, McCauley RA, Dexter DW, Hudes GR. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. · Br J Cancer. · Pubmed #11531260 links to  free full text

Abstract: Increases of individual beta tubulin isotypes in antimicrotubule drug resistant cell lines have been reported by several laboratories. We have previously described elevations in beta(III)and beta(IVa)isotypes in estramustine and paclitaxel resistant human prostate carcinoma cells. To investigate further the function of beta tubulin isotypes in antimicrotubule drug response, human prostate carcinoma cells that normally have very low to undetectable levels of beta(III)were stably transfected with beta(III)cDNA in pZeoSV system. An 18 bp haemagglutinin (HA) epitope tag was added at the 3' end prior to cloning into the vector. Cells were transfected with pZeoSV or pZeoSV-beta(III)plasmids and selected in the presence of Zeocin. Immunofluorescent staining of the transfectant cells have shown significant expression and incorporation of HA-tagged beta(III)tubulin into cellular microtubules. Quantitation of Western blots revealed the HA-tagged beta(III)levels to be approximately 7-fold higher than the vector control cells. RT-PCR analysis confirmed the increase at the transcript level and also revealed a collateral increase of beta(II)and beta(IVb)transcripts. Cell viability assays indicated that sensitivity of beta(III)transfected cells to various antimicrotubule agents was similar to vector transfected cells: IC50 values for estramustine, paclitaxel, colchicine and vinblastine were 4 microM, 4 nM, 22 nM and 2 nM, respectively for both cell lines. Thus, overexpression of beta(III)isotype in human prostate carcinoma cells by stable transfection failed to confer antimicrotubule drug resistance to these cells. Counterregulatory increases of endogenous beta(II)and beta(IVb)tubulin isotypes in these beta(III)transfected cells may be a compensatory mechanism used by the cells to overcome the effects of elevated beta(III)levels on the cellular microtubules. These results highlight the difficulty in isolating the contribution of single tubulin isotypes in drug response studies.

Freedman GM, Negendank WG, Hudes GR, Shaer AH, Hanks GE. · Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. · Urology. · Pubmed #10414737 No free full text.

Abstract: OBJECTIVES: To compare the accuracy of a bone marrow magnetic resonance imaging (MRI) protocol in patients at high risk of metastatic disease with radioisotopic bone scans, the standard method for detection of bony metastases in patients with prostate cancer. METHODS: The study group consisted of 19 men with prostate cancer who underwent a bone marrow MRI between November 1993 and February 1996. This protocol images the marrow of the thoracolumbar spine, sacrum, pelvis, and femurs. Indications for MRI included an equivocal bone scan and/or staging of locally advanced or recurrent disease. The findings on MRI and bone scan were compared and the results correlated with the subsequent clinical patient outcome. RESULTS: The bone marrow MRI protocol detected metastatic disease in 1 (7%) of 13 patients with negative bone scans. Four patients had an indeterminate bone scan: 2 had true-positive MRIs, 1 a true-negative MRI, and 1 a false-positive MRI on the basis of subsequent clinical follow-up. Two patients with positive bone scans had true-positive MRIs. CONCLUSIONS: Although not recommended for routine staging, MRI was useful in this study for clarifying an equivocal bone scan. The bone marrow MRI protocol images a high yield volume of the bony skeleton and is fast and economical compared with obtaining many focused MRI scans of these areas separately. These preliminary data suggest that further investigation of its clinical utility for staging locally advanced or recurrent disease is justified.