SPOREs
Prostate
Projects
Projects
Project 4: Modulating Transcription Factor Targets Via Chemical Genomics
Co-Principal Investigators:
Todd Golub, MD
Mary-Ellen Taplin, MD
Participating Institution(s):
Dana-Farber Cancer Institute
Massachusetts Institute of Technology (Broad Institute)
Project 4: Specific Aims
The Specific Aims of this project are:
1) To design and open and clinical trial aimed at testing the hypothesis that clinical benefit in prostate cancer could be achieved by abrogating androgen receptor (AR) activity via inhibition of heat shock protein 90 (HSP90), which we showed in the prior funding period to be required for AR protein stability
2) To develop a gene expression signature of activity of TMPRSS2/ERG that would be amenable to high throughput small molecule screening.
Project 4: Studies and Results
In Aim 1, we proposed to design and open and clinical trial aimed at testing the hypothesis that clinical benefit in prostate cancer could be achieved by abrogating androgen receptor (AR) activity via inhibition of heat shock protein 90 (HSP90), which we showed in the prior funding period to be required for AR protein stability. We have made excellent progress toward that goal. Specifically, we have written (and have received IRB approval for) a clinical trial testing the small molecule compound IPI-504, a potent, selective, and reversible inhibitor of Hsp90. IPI-504 is a novel analog of 17-AAG, a derivative of the natural product geldanamycin. IPI-504 is > 4000x more soluble than 17-AAG in aqueous formulations, and has > 200 mg/mL solubility. In addition, IPI-504 and 17-AAG interconvert in vitro and in vivo.
A multi-center, open-label, Phase 2 trial was designed to investigate the clinical activity and pharmacodynamics of IPI-504 in patients with CRPC stratified by prior chemotherapy. The study employs a two-stage design with PSA and radiographic response rates as primary endpoints. Secondary endpoints include changes in intratumoral client protein levels as well as changes in circulating tumor cells and circulating Her-2 levels. Patients are being enrolled in two groups (n=15 patients per group), determined by prior exposure to systemic cytotoxic chemotherapy as follows:
Group A (15 patients): No prior treatment for prostate cancer with cytotoxic chemotherapy (adjuvant or neoadjuvant chemotherapy is acceptable if completed >2 years prior to study).
Group B (15 patients): Must have radiographic evidence of disease; Must have been treated with a docetaxel-based chemotherapy regimen for CRPC with a minimum of two cycles with either PSA or RECIST defined radiographic progression during or within 60 days of completing docetaxel-based chemotherapy or be intolerant of docetaxel-based chemotherapy.
If a PSA response or a radiographic RECIST response is observed in one patient in either Group A or Group B, an additional 10 patients will be added to that cohort. A total of 30-50 patients are planned for enrollment, depending on the expansion of the dose groups. A schematic of the trial design is provided in the figure above
Doses are administered twice weekly for two weeks (at least ≥ 72 hours apart) followed by 10 days off treatment. At the end of 12 weeks of treatment (4 cycles), patients are evaluated for evidence of clinical improvement or stabilization. Patients without evidence of progression may continue on trial. Since the trial was first activated in November 2007, a total of 19 patients have been screened for participation at 5 sites nationally, including 3 at Dana-Farber/ Harvard Cancer Center. Nine patients in total have been treated, 2 in arm A and 7 in arm B. Three patients are currently being screened. Accrual is ongoing at all sites. We therefore remain on track with the goals of Aim 1.
In Aim 2, we proposed to develop a gene expression signature of activity of TMPRSS2/ERG that would be amenable to high throughput small molecule screening. The proposed small molecule screen was more ambitious than prior screens performed in our laboratory because 1) we proposed to not constrain the size of the signature to 100 transcripts (the prior limit of the technology), and 2) we proposed to screen > 10X more compounds than we had previously attempted. These goals require a significant amount of assay development, and we have accordingly focused on these issues during this past year. Specifically, we have made excellent progress in developing a Luminex-bead based assay capable of profiling 600 transcripts in a single well of a standard 384-well plate at a reagent cost of ~ $1. We have begun preliminary testing of this capability by analyzing the gene expression signature induced by HSP90 inhibitors (being studied clinically in Aim 1). This 600-plex signature successfully captures the cellular activity of HSP90 inhibitors when compared to their genome-wide profiles using the Connectivity Map, thereby validating our ability to reproducibly measure signatures of up to 600 genes in a manner compatible with high throughput screening. This result indicates that we will be able to define a signature of TMPRSS2/ERG activity containing as many as 600 transcripts – far beyond to our initial expectations.
In addition, in anticipation of the need to perform high throughput gene expression-based signature screens, we have made significant progress in adapting the screening method to the high throughput screening, having successfully automated several of the steps in the process that previously were done manually (and therefore were both time-intensive and prone to human error). This suggests that we will be well-positioned to begin formal high throughput screening against a refined (and possibly expanded) TMPRSS2/ERG signature in the year ahead.
Project 4: Significance
The IPI-504 clinical trial should establish whether HSP90 inhibition is a clinically attractive approach to the treatment of prostate cancer. The small molecule screening efforts hold the promise to identify new drug leads that have potential as entirely novel approaches to the treatment of prostate cancer, focusing on the molecule defects that underlie the disease.
Project 4: Plans
We plan to continue enrollment on the IPI-504 trial over the year ahead, and also continue (as proposed) on the development of a signature of TMPRSS2/ERG activity that is suitable for high throughput screening. We anticipate that we will be ready to begin small molecule screening by the end of the funding year ahead.
Project 4: Publications
Identification of prostate cancer modifier pathways using parental strain expression mapping.
Xu Q, Majumder PK, Ross K, Shim Y, Golub TR, Loda M, Sellers WR. Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17771-6. Epub 2007 Oct 31. PMID: 17978178 [PubMed - indexed for MEDLINE]
Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators.
Hieronymus H, Lamb J, Ross KN, Peng XP, Clement C, Rodina A, Nieto M, Du J, Stegmaier K, Raj SM, Maloney KN, Clardy J, Hahn WC, Chiosis G, Golub TR. Cancer Cell. 2006 Oct;10(4):321-30. Epub 2006 Sep 28.
Project 4: Project-Generated Resources
None to date.
