1. Studies related to drug resistance. During my initial training under a KO8 Award, I carried out studies with multidrug resistant and methotrexate-resistant Chinese hamster lung fibroblast cell lines in the laboratory of Dr. P. Melera. I was involved in the identification of full-length and splice variants of p-glycoprotein. I also developed expression vectors using a novel mutant form of dihydrofolate reductase to express high levels of intracellular calcium transport ATPase and human thyrotropin via methotrexate selection for biochemical studies. This training enabled me to set up my own laboratory where I carried out my first independent studies related to inhibitors of intracellular calcium transport ATPase, which was being evaluated by other investigators as a potential therapeutic target in prostate cancer. I was the first to develop and study mammalian cell lines resistant to thapsigargin, a highly potent and specific inhibitor of intracellular calcium ATPases. I showed that alterations in calcium ATPase expression via transcriptional upregulation or gene amplification—and/or alterations in p-glycoprotein expression—mediated resistance to thapsigargin in several cell culture models, including prostate cancer. I also identified a hot spot for point mutations in the thapsigargin binding domain and several mutants of calcium ATPase that can contribute to the drug-resistant phenotype.
a. Gutheil JC, Hart SR, Belani CP, Melera PW, Hussain A. Alterations in Ca2+ transport ATPase and P-glycoprotein expression can mediate resistance to thapsigargin. J Biol Chem. 1994 Mar 18;269(11):7976–81. PubMed PMID: 7907587.
b. Hussain A, Garnett C, Klein MG, Tsai-Wu JJ, Schneider MF, et al. Direct involvement of intracellular Ca2+ transport ATPase in the development of thapsigargin resistance by Chinese hamster lung fibroblasts. J Biol Chem. 1995 May 19;270(20):12140–6. PubMed PMID: 7744863.
c. Yu M, Zhong L, Rishi AK, Khadeer M, Hussain A, et al. Specific substitutions at amino acid 256 of the sarcoplasmic/endoplasmic reticulum Ca2+ transport ATPase mediate resistance to thapsigargin in thapsigargin-resistant hamster cells. J Biol Chem. 1998 Feb 6;273(6):3542–6. PubMed PMID: 9452480.
d. Lee DI, Sumbilla C, Lee M, Natesavelalar C, Hussain A, et al. Mechanisms of resistance and adaptation to thapsigargin in androgen-independent prostate cancer PC3 and DU145 cells. Arch Biochem Biophys. 2007 Aug 1;464(1):19–27. PubMed PMID: 17475205.
2. Preclinical studies on multimodal targeting of prostate cancer. Given that castration-resistant prostate cancer is a relatively chemo-resistant state, my laboratory has used LNCaP- based SCID mouse xenografts to evaluate optimal integration of docetaxel and androgen deprivation therapy (ADT) in the treatment of prostate cancer. This work demonstrated that docetaxel when used early (i.e., pre-ADT or concurrent with ADT) provides better antitumor effects than when used after ADT. In other studies using TRAMP mice, I have shown that differential expression of certain antiapoptotic and stress response proteins occurs at different time points post ADT, thus providing a potential time window to target these proteins to enhance antitumor activity of ADT. In addition, my laboratory is the first to show that not only ADT but also docetaxel chemotherapy can lead to the development of neuroendocrine carcinoma in TRAMP mice, suggesting that the cellular stress of antitumor therapies resulting in neuroendocrine carcinoma may possibly contribute to treatment failure. My group has also shown that telomere and microtubule targeting with arsenicals and taxanes, respectively, has synergistic antiproliferative activity in both wild-type and taxane-resistant cell culture models of prostate cancer.
a. Tang Y, Khan MA, Goloubeva O, Lee DI, Hussain A, et al. Docetaxel followed by castration improves outcomes in LNCaP prostate cancer-bearing severe combined immunodeficient mice. Clin Cancer Res. 2006 Jan 1;12(1):169–74. PubMed PMID: 16397039.
b. Tang Y, Wang L, Goloubeva O, Khan MA, Hussain A, et al. Divergent effects of castration on prostate cancer in TRAMP mice: possible implications for therapy. Clin Cancer Res. 2008 May 15;14(10):2936–43. PubMed PMID: 18483360.
c. Tang Y, Wang L, Goloubeva O, Khan MA, Hussain A, et al. The relationship of neuroendocrine carcinomas to anti-tumor therapies in TRAMP mice. Prostate. 2009 Dec 1;69(16):1763–73. PubMed PMID: 19691128.
d. Zhang B, Suer S, Livak F, Adediran S, Hussain A, et al. Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells. Mol Pharmacol. 2012 Aug;82(2):310–21. PubMed PMID: 22584221.
3. Investigator-initiated multimodal clinical trials in prostate cancer. As a trialist, I have conducted a number of clinical trials in prostate cancer that have led to multiple joint publications with other investigators across different institutions, reflecting the contributions of the Hormone Responsive Cancers program to the broader clinical effort in genitourinary cancers at the national level. In addition, I have developed, conducted, and carried to completion investigator-initiated clinical trials in recurrent and high-risk prostate cancer, including Phase II studies that were the first to evaluate the role of sequential docetaxel and ADT in castration-sensitive prostate cancer recurring after definitive local therapies, and concurrent paclitaxel, radiation therapy and ADT in high risk prostate cancer given as primary therapy or in the adjuvant or salvage setting post prostatectomy. I have also actively contributed to an investigator-initiated trial developed at Dana-Farber Cancer Institute that evaluated docetaxel, ADT, and bevacizumab in patients experiencing biochemical failure after primary local therapies for prostate cancer. These studies have established the feasibility of multimodality treatments in the above disease states of prostate cancer.
a. Hussain A, Dawson N, Amin P, Engstrom C, Dorsey B, et al. Docetaxel followed by hormone therapy in men experiencing increasing prostate-specific antigen after primary local treatments for prostate cancer. J Clin Oncol. 2005 Apr 20;23(12):2789–96. PubMed PMID: 15837994.
b. Dibiase SJ, Hussain A, Kataria R, Amin P, Bassi S, et al. Long-term results of a prospective, Phase II study of long-term androgen ablation, pelvic radiotherapy, brachytherapy boost, and adjuvant docetaxel in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):732–6. PubMed PMID: 21036486.
c. Hussain A, Wu Y, Mirmiran A, DiBiase S, Goloubeva O, et al. Long-term follow-up of a prospective trial of trimodality therapy of weekly paclitaxel, radiation, and androgen deprivation in high-risk prostate cancer with or without prior prostatectomy. Int J Radiat Oncol Biol Phys. 2012 Jan 1;82(1):167–74. PubMed PMID: 21036487.
d. McKay RR, Gray KP, Hayes JH, Bubley GJ, Hussain A, et al. Docetaxel, bevacizumab, and androgen deprivation therapy for biochemical disease recurrence after definitive local therapy for prostate cancer. Cancer. 2015 Apr 22. PubMed PMID: 25903013.
4. Population-based studies in prostate cancer using Surveillance, Epidemiology, and End Results (SEER)-Medicare datasets. Using the NCI SEER cancer registry linked to Medicare claims data, our group has demonstrated that a proportion of patients diagnosed with incident prostate cancer do not undergo subsequent staging, and that African Americans and older patients have statistically significant lower odds ratios for being staged than non-Hispanic Whites or younger patients. Further, among those staged, African Americans and older patients are more likely to be diagnosed with metastatic disease. In addition, we have demonstrated that although men with incident stage IV prostate cancer have similar odds ratios for post-urologist medical oncologist/hematologist visits, African Americans and elderly men are less likely to receive chemotherapy for advanced prostate cancer. We have also found that in men diagnosed with stage I–III prostate cancer, racial disparities in post-diagnosis urologist visits is impacted not only by patient-level factors but also by variations at the community level. In an effort to understand the impact of advanced prostate cancer on the extent and types of health services used, in other studies we have identified and quantified health services utilization among such men.
a. Mullins CD, Onukwugha E, Bikov K, Seal B, Hussain A. Health disparities in staging of SEER-Medicare prostate cancer patients in the United States. Urology. 2010 Sep 76(3):566–72. PubMed PMID: 20163844; PubMed Central PMCID: PMC3736596.
b. Onukwugha E, Mullins CD, Hsu VD, Seal B, Hussain A. Effect of urologists and medical oncologists on treatment of elderly men with Stage IV prostate cancer. Urology. 2011 May 77(5):1088–95. PubMed PMID: 21439617.
c. Yong C, Onukwugha E, Mullins CD, Seal B, Hussain A. The use of health services among elderly patients with stage IV prostate cancer in the initial period following diagnosis. J Geriatr Oncol. 2014 Jul 5(3):290–8. PubMed PMID: 24780283.
d. Onukwugha E, Osteen P, Jayasekera J, Mullins CD, Hussain A, et al. Racial disparities in urologist visits among elderly men with prostate cancer: a cohort analysis of patient-related and county of residence-related factors. Cancer. 2014 Nov 1;120(21):3385–92. PubMed PMID: 24962590.
Update Your Profile