Activity In Prostate Cancer Models Research Articles

A phase 1/2 study of ONCT-534, a dual-action androgen receptor inhibitor (DAARI), in patients with metastatic castration-resistant prostate cancer.

TPS241 Background: Current therapeutic strategies for metastatic castration-resistant prostate cancer (mCRPC) include treatment with next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide, darolutamide, and apalutamide, which all target the ligand-binding domain (LBD) of the AR, and abiraterone, an androgen biosynthesis inhibitor. Approximately 5% to 10% of patients will have primary resistance to ARSIs and most initial responders will develop resistance within 1 to 3 years. Eventually, nearly all men with prostate cancer treated with ARSIs develop resistance via several mechanisms including activation of AR genomic alterations, epigenetic alterations, and expression of truncated constitutively active AR splice variants. Hence, there is substantial unmet need for treatment of men with mCRPC resistant to at least one next-generation ARSI. ONCT-534 is a DAARI with a novel mechanism of action that combines inhibition of AR function with degradation of the AR protein. Importantly, this activity includes interaction with the N-terminal domain (NTD), rendering it effective against splice variants and LBD mutants, unlike existing ARSIs. ONCT-534 has demonstrated preclinical activity in prostate cancer models against unmutated AR and multiple forms of AR alteration, including amplification, mutations in the LBD, and splice variants with loss of LBD. Methods: ONCT-534-101 is a phase 1/2, multi-center study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of ONCT-534 in subjects with mCRPC without neuroendocrine differentiation or small cell features who have relapsed or are refractory (R/R) to at least one next-generation ARSI. The study will be separated into a Phase 1 Dose Escalation and a Phase 2 Dose Expansion. The Phase 1 portion will evaluate approximately 27 subjects in 5 dose levels using an adaptive Bayesian Optimal Interval (BOIN) design to assess safety, tolerability and DLT at escalating doses and to determine the MTD and inform the 2 dose levels or schedules to be tested in Phase 2. DLTs will be assessed during the first 28 days of treatment. The AR phenotype and AR levels of each subject’s disease will be evaluated pre- and post-treatment. The Phase 2 portion will evaluate approximately 32 subjects in 2 randomized cohorts to assess safety and tolerability of ONCT-534, compare the 2 different dose levels or schedules to select the optimal dose for further study, and assess the preliminary antitumor activity of ONCT-534. In both phases, after a screening period, eligible subjects with mCRPC will receive their assigned dose regimen of ONCT-534, which will be administered orally daily for 2 years or until disease progression and no longer clinically benefiting from treatment or development of unacceptable toxicity. The study was opened for enrollment September 2023. Clinical trial information: NCT05917470 .

Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models.

Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta-analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta-analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta-analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.

Starving lethal prostate cancer by targeting heat shock proteins and glycolytic enzymes

Metastatic prostate cancer remains uncurable. In this issue of Cell Reports Medicine, Rice et al. present an assessment of a compound (SU086) demonstrating activity in prostate cancer models through heat shock protein 90 inhibition and cell metabolism changes.

Abstract 1131: ORIC-944, a potent and selective allosteric PRC2 inhibitor, demonstrates robust in vivo activity in prostate cancer models

Abstract The polycomb repressive complex 2 (PRC2) is responsible for the methylation of histone 3 at lysine 27 (H3K27) which leads to long-term transcriptional silencing. Through this epigenetic chromatin silencing mechanism, PRC2 plays a key role in regulating cellular functions such as cell growth and differentiation. PRC2 comprises three core subunits: the catalytic subunit enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12). EED directly interacts with histone H3K27me3 and is essential for the histone methyltransferase activity of PRC2. PRC2 dysregulation occurs in multiple solid tumors and hematological malignancies, resulting in elevated levels of PRC2 activity and H3K27 trimethylation, and has been linked to poor prognosis in patients with metastatic prostate cancer. First-generation PRC2 inhibitors which target EZH2 have demonstrated clinical activity in several cancers, yet the pharmacological and ADME properties of these compounds require high doses that only achieve partial target inhibition at clinically active levels and exhibit drug-drug interaction (DDI) liabilities. As an alternative strategy to fully inhibit the PRC2 complex, we developed ORIC-944, a potent and highly selective allosteric inhibitor of PRC2 via binding the EED subunit. This unique EED targeting strategy can more completely inhibit PRC2, for example, in the presence of innate or acquired resistance mutations in EZH2, and by addressing the potential compensatory escape mechanism of EZH1-driven tumor growth. ORIC-944 has potential best-in-class drug properties compared to first generation PRC2 inhibitors, including superior potency and improved DDI liabilities. In diffuse large B-cell lymphoma (DLBCL) xenografts in vivo, ORIC-944 significantly depleted H3K27 trimethylation and induced tumor regressions in a dose-dependent manner. ORIC-944 demonstrated strong tumor growth inhibition as a single agent with once daily oral dosing in both enzalutamide-responsive and enzalutamide-resistant prostate cancer models. ORIC-944 caused a significant reduction in tumor cell proliferation and anti-apoptotic signaling, as measured by Ki67 and survivin, respectively. Moreover, in PK/PD assessments, ORIC-944 strongly depleted H3K27me3 in treated tumors. These in vivo studies established that effective single agent inhibition of PRC2 via EED results in decreased tumor cell growth in PRC2-dependent prostate cancer models. In summary, ORIC-944 is a potent, highly selective, allosteric, orally bioavailable PRC2 inhibitor via the EED subunit that represents a differentiated strategy to block PRC2 activity in selected cancers. We are developing ORIC-944 as a best-in-class PRC2 inhibitor for the treatment of patients with advanced prostate cancer and expect to file an IND in the second half of 2021. Citation Format: Anneleen Daemen, Jessica D. Sun, Aleksandr Pankov, Frank L. Duong, Natalie Yuen, Shravani Barkund, Shelly Kaushik, Jae H. Chang, David M. Briere, Niranjan Sudhakar, Andrew Calinisan, Aaron Burns, John M. Ketcham, Matthew A. Marx, Peter Olson, James G. Christensen, Melissa R. Junttila, Lori S. Friedman. ORIC-944, a potent and selective allosteric PRC2 inhibitor, demonstrates robust in vivo activity in prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1131.

Abstract 1393: PSMA-Targeted Thorium Conjugate (BAY 2315497) and olaparib combination show synergistic anti-tumor activity in prostate cancer models

Abstract The PSMA targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) is a novel targeted alpha therapy (TAT) approach which is currently under investigation in a FiH trial in patients with metastatic castration resistant prostate cancer (mCRPC; NCT03724747). It consists of the alpha emitter thorium-227 complexed to a 3,2-HOPO chelator conjugated to a PSMA targeting antibody delivering radiation to PSMA expressing tumor cells and their microenvironment resulting in the induction of potentially cytotoxic DNA double-strand breaks (DBS). Combining with the PARP inhibitor olaparib may act synergistically via inhibition of DDR pathways. Here we evaluated the efficacy of PSMA-TTC in combination with olaparib that demonstrated a positive outcome in patients with homologous recombination repair-mutated mCRPC. We explored potential synergies of the combination treatment in prostate cancer models in vitro and in vivo and studied the mode of action by protein and RNA analysis. In vitro, synergy of the combination of PSMA-TTC with olaparib with a combination index (CI) of 0.7 was observed in three cell lines, namely LNCaP, 22Rv1 and MDA-PCa2b. with the first two (LNCaP and 22Rv1) carrying mutations in BRCA2. Only moderate synergy with a CI of 0.8 was seen in BRCA2 wt VCaP cells. In vivo, dose dependent anti-tumor activity with single i.v. injections of PSMA-TTC at 150 and 300 kBq/kg was seen in the LNCaP prostate cancer model resulting in a tumor/control (T/C) ratio of 0.3 and 0.09 at day 28, respectively. In contrast, olaparib given at 50 mg/kg QD did not show activity at day 28. The 300 kBq/kg PSMA-TTC dose combined with olaparib showed the most pronounced anti-tumor activity (T/C=0.04) and significantly increased the number of animals with complete tumor regressions compared to high dose PSMA-TTC alone (6 CRs vs 2 CRs, p = 0.0397, Chi-square) on day 28. At the end of the consecutive surveillance period on day 117, 7/8 (87.5%) animals remained tumor-free (putatively cured) in the combination group vs 4/10 (40%) mice in the PMSA-TTC monotherapy group (Chi-square test, P = 0.0400). Additive or synergistic toxicological effects for the combination treatment were not seen based on body weight loss and fatal tox rate. At the 117-day time point both the 300 kBq/kg PSMA-TTC monotherapy and combination with olaparib group demonstrated 0.3% and 9.3% body weight gain indicating good tolerability. Changes in markers of DNA damage response following treatment will be presented. In summary, combination of PSMA-TTC with olaparib shows synergistic preclinical anti-tumor activity and support further clinical investigation of this combination treatment in prostate cancer patients. Citation Format: Christoph A. Schatz, Stefanie Hammer, Antje Wengner, Urs B. Hagemann, Dominik Mumberg, Arne Scholz. PSMA-Targeted Thorium Conjugate (BAY 2315497) and olaparib combination show synergistic anti-tumor activity in prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1393.

Abstract 5663: Affinity tuned XmAb®2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models

Abstract Bispecific antibodies enable therapeutic modalities inaccessible to traditional mAbs, such as T cell engagers that bind both CD3 on T cells and a target antigen on tumor cells. These agents provide synthetic immunity by expanding, activating, and redirecting T cells against a target of interest. While targeting lineage-restricted antigens such as CD19 or CD20 have found clinical success in hematopoietic cancers, targeting solid tumors requires high expressing tumor associated antigens (TAAs) with minimal normal tissue expression. Prostate cancer (PC) is one of the most prevalent cancers in men, and end stage (castration-resistant prostate cancer) has no curative treatment option. Prostate specific membrane antigen (PSMA), a type II transmembrane protein with a large extracellular domain, has long generated interest as a therapeutic target. It is highly overexpressed in PC compared to normal tissue, and its expression has been shown to correlate with malignancy. Previous attempts to target PSMA include antibody-based radiotherapy and antibody drug conjugates, which have shown some success but can be hampered by the inherent toxicity of the modality. Building upon the XmAb® heterodimeric Fc platform, we generated bispecific antibodies in an XmAb 2+1 Fab2-scFv-Fc format that are bivalent for PSMA and monovalent for CD3. Reducing the affinity of both specificities encouraged avid binding and strong activity on high PSMA expressing cell lines while minimizing reactivity on low expressing cell lines, matching PSMA's differential expression pattern. To ensure biologically valid antigen densities were being considered, IHC was conducted on paraffin embedded arrays of tumor tissue, normal tissue, and cell lines. Upon matching the staining intensity between the three sample types, we identified cell lines with corresponding PSMA antigen density that could serve as proxies of tumor and normal tissue. In vitro T cell-dependent cellular cytotoxicity (TDCC) assays on the relevant cell lines confirmed selective potency on high versus low expressing cells. Citation Format: Alex Nisthal, Matthew Dragovich, Erik W. Pong, Veronica Zeng, Michael Hedvat, Christine Bonzon, Kendra Avery, Rumana Rashid, Connie Ardila, Umesh S. Muchhal, Gregory L. Moore, Seung Y. Chu, John R. Desjarlais. Affinity tuned XmAb®2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5663.

Abstract B006: Targeting EZH2 increases therapeutic efficacy of PD-1 blockade in models of prostate cancer

Abstract Prostate cancers are considered immunologically ‘cold’ tumors as they have demonstrated poor response to check-point inhibitor therapy (CPI). Recently, enrichment of interferon response genes suggests a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models increases expression of double-strand RNA (dsRNA), that is associated with upregulation of genes connected with antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response genes, including PD-L1. Likewise, application of a novel EZH2 derived gene signature and TMA analysis indicated an inverse correlation between tumor EZH2 activity/expression with, T-cell inflamed and IFN gene signatures, and PD-L1 expression in human prostate cancer samples. EZH2 inhibition combined with PD-1 CPI significantly enhances anti-tumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI. Citation Format: Anjali Sheahan, Katherine Morel, Deborah Burkhart, Sylvan Baca, David Labbè, Keven Roehle, Carla Calagua, Huihui Ye, Phillip Galbo, Sukanya Panja, Antonina Mitrofanova, Anis Hamid, Adam Kibel, Atish Choudhury, Mark Pomerantz, Matthew Freedman, Christopher Sweeney, Stephanie Dougan, Adam Sowalsky, Brian Olson, Massimo Loda, Leigh Ellis. Targeting EZH2 increases therapeutic efficacy of PD-1 blockade in models of prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B006. doi:10.1158/1535-7163.TARG-19-B006

Minireview: SLCO and ABC transporters: a role for steroid transport in prostate cancer progression.

Androgens play a critical role in the development and progression of prostate cancer (PCa), and androgen deprivation therapy via surgical or medical castration is front-line therapy for patients with advanced PCa. However, intratumoral testosterone levels are elevated in metastases from patients with castration-resistant disease, and residual intratumoral androgens have been implicated in mediating ligand-dependent mechanisms of androgen receptor activation. The source of residual tissue androgens present despite castration has not been fully elucidated, but proposed mechanisms include uptake and conversion of adrenal androgens, such as dehdroepiandrosterone to testosterone and dihydrotestosterone, or de novo androgen synthesis from cholesterol or progesterone precursors. In this minireview, we discuss the emerging evidence that suggests a role for specific transporters in mediating transport of steroids into or out of prostate cells, thereby influencing intratumoral androgen levels and PCa development and progression. We focus on the solute carrier and ATP binding cassette gene families, which have the most published data for a role in PCa-related steroid transport, and review the potential impact of genetic variation on steroid transport activity and PCa outcomes. Continued assessment of transport activity in PCa models and human tumor tissue is needed to better delineate the different roles these transporters play in physiologic and neoplastic settings, and in order to determine whether targeting the uptake of steroid substrates by specific transporters may be a clinically feasible therapeutic strategy.

Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen bicalutamide in prostate cancer models.

Although androgen ablation therapy is the foundation of current prostate cancer treatment, most patients ultimately develop castration-resistant disease. One proposed mechanism to account for androgen receptor (AR) activity in the castrate environment is via crosstalk with other signaling pathways. Specifically, reciprocal interactions between the AKT/mTOR and AR pathways have been implicated in prostate cancer progression. Here, we used the potent inhibitor ridaforolimus to target mTOR signaling alone and in combination with AR blockade by bicalutamide to examine the effect of abrogating these signaling pathways. Ridaforolimus treatment inhibited the proliferation of all six prostate cancer cell lines examined with the greatest sensitivity associated with loss of PTEN and elevated AKT/mTOR pathway activity. Dual inhibition of the AR and mTOR signaling pathways provided further benefit with the ridaforolimus-bicalutamide combination producing synergistic antiproliferative effects in prostate cancer cells in vitro when compared with each agent alone. Pharmacodynamic analysis confirmed that combination treatment resulted in full inhibition of each of the respective pathways. Importantly, the ridaforolimus-bicalutamide combination exhibited potent anti-tumor activity with parallel reductions in plasma PSA levels in vivo. Taken together, ridaforolimus exhibited potent antiproliferative and antitumor activity in prostate cancer models and the addition of bicalutamide represents a potentially effective combination strategy for patient therapy.

Vinflunine (VFL) as salvage chemotherapy in hormone-refractory prostate cancer (HRPC)

16059 Background: Two randomized, phase III trials have demonstrated survival benefits for docetaxel-based chemotherapy in patients (pts) with HRPC. Though some pts retain sensitivity to this agent after completion of therapy, progression of their disease eventually occurs. To date, there is no second-line therapy with proven survival benefits. VFL is a novel vinca alkaloid with demonstrated preclinical antitumor activity in prostate cancer models, and clinical activity in several solid tumors including breast and bladder cancer. In this multicenter phase II trial, we evaluated VFL as salvage chemotherapy in HRPC. Methods: Eligibility criteria: progressive hormone-refractory metastatic or incurable localized prostate carcinoma; ECOG PS 0–2; prior docetaxel; ≤ 2 prior chemotherapy regimens; no prior anthracycline; adequate bone marrow, kidney and liver function; informed consent. All pts received: VFL 320 mg/m2 IV every 3 weeks (280 mg/m2 for pts ECOG PS 2, GFR < 60 cc/min, or prior pelvic RT). Pts were reevaluated after 2 cycles (6 weeks); responding/stable pts received 6 cycles. This study was designed to detect a response rate > 15%; 4 responses in the first 26 evaluable pts were necessary to proceed to the second stage. Results: Between May 2007 and November 2007, 35 pts were enrolled: median age, 75 years (range 52–86); ECOG 0/1/2, 6/26/3 pts; bone metastases, 33 pts (94%); measurable disease, 14 pts (40%); > 1 prior chemotherapy regimen, 23 pts (66%). Pts received VFL for a mean of 2.6 cycles (range 1–6). 27 pts were evaluable for PSA response: 1 pt had a partial response (4%), 9 pts (33%) had stable disease, and 17 pts (63%) had progression. The single PSA responder also had an objective PR. Eight pts were inevaluable (too early, 6; withdrew from study for personal reasons, 2). Most patients progressed rapidly; only 32% were progression-free at 3 months. Grade 3/4 toxicities included neutropenia (40%), fatigue (14%), dehydration (11%), anemia (9%), and abdominal pain/cramping (6%). No treatment-related deaths occurred. Conclusions: VFL has minimal activity in heavily pretreated pts with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Genentech Bristol-Myers Squibb Bristol-Myers Squibb, Eli Lilly and Company, Genentech, GlaxoSmithKline, GPC Biotech, sanofi-aventis, SCRI

Rationale for zoledronic acid therapy in men with hormone-sensitive prostate cancer with or without bone metastasis

Men with prostate cancer are at risk for bone loss and skeletal complications throughout the course of their disease. Bone loss is prevalent in many men with prostate cancer at initial diagnosis, and initiating androgen deprivation therapy results in accelerated bone resorption, leading to bone loss and an increased risk of fracture. These men are also at high risk for disease progression and bone metastases that can result in significant skeletal morbidity, including pathologic fracture, spinal cord compression, and debilitating bone pain requiring additional therapy. Excessive osteoclast activity plays a central role in the pathophysiology of bone disease at each stage of prostate cancer disease progression. Zoledronic acid, a highly potent inhibitor of osteoclast-mediated bone resorption, has increased bone mineral density in men receiving androgen deprivation therapy and is the only bisphosphonate that has shown statistically significant reductions in skeletal morbidity in patients with bone metastases from prostate cancer. Furthermore, preclinical evidence suggests that zoledronic acid has antitumor activity in prostate cancer models. Recently, a treatment algorithm was developed by the 3rd International Consultation on Prostate Cancer recommending the use of zoledronic acid for the prevention of skeletal complications in patients with bone metastases from prostate cancer, regardless of their hormone status, and for the prevention of treatment-induced bone loss in patients without evidence of bone metastases. According to this algorithm, zoledronic acid should be considered for the prevention of skeletal morbidity in patients with prostate cancer throughout their treatment continuum.

Phase I/II trial of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer

4654 Background: Docetaxel is a microtubule stabilizing agent with documented clinical activity in patients with advanced prostate cancer. Bortezomib (Velcade, formerly PS-341) is a small molecule that is a potent and reversible proteasome inhibitor with evidence of anti-tumor activity in prostate cancer models. Following completion of the phase I portion of this study during which MTD was not reached, we evaluated two dose levels in expanded phase II cohorts. We report the results from the low expanded cohort. Methods: From 6/02 to 4/03, 31 patients (pts) were enrolled. Eligible pts had androgen-independent prostate cancer with radiologic and/or biochemical evidence of progression following antiandrogen withdrawal with castrate testosterone levels, KPS ≥ 60% and adequate organ function; prior systemic therapy was permitted. Docetaxel with standard dexamethasone premedication was given at 40 mg/m2 IV over 30 minutes on days 1 and 8. Bortezomib was given 24 hours after docetaxel at of dose of 1.3 mg/m2 IV push on days 2 and 9. Treatment was repeated every 21 days. Results: Median age was 67 (53–81), median KPS was 85% (60–90%), and median pre-therapy PSA value was 270. Nineteen pts had prior chemotherapy, 14 with a taxane containing regimen. Therapy was well tolerated with grade 3 diarrhea, peripheral neuropathy, hyperglycemia, neutropenia and fatigue seen in less than 5% of patients. Twenty-two patients are currently evaluable for response. Eight of 22 (36%) (90% CI 20–56) had a ≥ 50% decline in PSA from baseline and 5 of the 8 had a 90% or greater decline. Two of 12 (17%) patients with measurable disease achieved a partial response. Conclusions: Docetaxel + bortezomib was well tolerated at this dose and schedule, and showed promising activity in this population. Evaluation of a cohort receiving docetaxel at 40 mg/m2 + bortezomib 1.6 mg/m2 is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Millennium Pharmacueticals Glaxo Aventis; Celgene AstraZeneca; Aventis; Genentech; Millennium