Sites Of Metastatic Prostate Cancer Research Articles

Clinical Trial Protocol for VIOLET: A Single-Center, Phase I/II Trial Evaluation of Radioligand Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer with [161Tb]Tb-PSMA-I&T.

[177Lu]Lu-PSMA is an effective class of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response may be partially explained by the presence of micrometastatic deposits, which are energy-sheltered and receive low absorbed radiation with 177Lu due to the approximately 0.7-mm mean pathlength. 161Tb has abundant emission of Auger and conversion electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown invitro and invivo efficacy superior to that of 177Lu. We aim to demonstrate that [161Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 patients with mCRPC. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy (unless medically unsuitable) and androgen receptor pathway inhibitor; prostate-specific membrane antigen-positive disease on [68Ga]Ga-PSMA-11 or [18F]DCFPyL PET/CT (SUVmax ≥ 20); no sites of discordance on [18F]FDG PET/CT; adequate bone marrow, hepatic, and renal function; an Eastern Cooperative Oncology Group performance status of no more than 2, and no prior treatment with another radioisotope. The dose escalation is a 3 + 3 design to establish the safety of 3 prespecified activities of [161Tb]Tb-PSMA-I&T (4.4, 5.5, and 7.4 GBq). The maximum tolerated dose will be defined as the highest activity level at which a dose-limiting toxicity occurs in fewer than 2 of 6 participants. The dose expansion will include 24 participants at the maximum tolerated dose. Up to 6 cycles of [161Tb]Tb-PSMA-I&T will be administered intravenously every 6 wk, with each subsequent activity reduced by 0.4 GBq. The coprimary objectives are to establish the maximum tolerated dose and safety profile (Common Terminology Criteria for Adverse Events version 5.0) of [161Tb]Tb-PSMA-I&T. Secondary objectives include measuring absorbed radiation dose (Gy), evaluating antitumor activity (prostate-specific antigen 50% response rate, radiographic and prostate-specific antigen progression-free survival, overall survival, objective response rate), and evaluating pain (Brief Pain Inventory-Short Form) and health-related quality of life (Functional Assessment of Cancer Therapy-Prostate and Functional Assessment of Cancer Therapy-Radionuclide Therapy). Conclusion: Enrollment was completed in February 2024. Patients are still receiving [161Tb]Tb-PSMA-I&T.

Prostate Adenocarcinoma Metastasis to the Rectal Submucosa and Mesorectal Lymph Node on 18F-PSMA PET/CT.

We report a case of biopsy-proven prostate cancer metastasis to the rectum and presumed metastasis to a mesorectal lymph node, identified as radiotracer-avid lesions on prostate-specific membrane antigen PET/CT during workup for biochemically recurrent prostate cancer. This case adds to a growing number of atypical sites of metastatic prostate cancer being reported since the approval of prostate-specific membrane antigen PET/CT for staging of prostate cancer.

Abstract A061: Nuclear lamin content as a biomarker for prostate cancer progression

Abstract Lamins are proteins that help to structure the cellular nucleus via the formation of an intermediate filament weave that grants rigidity to the nuclear membrane. Lamins also tether the chromatin to the nuclear envelope, contributing to the formation of heterochromatin, necessary for adequate gene expression control. The purpose of this study was to use a combination of immunostaining, ChIP-seq, and chromosome conformation capture (Hi-C) to a) characterize the expression and deposition patterns of Lamin A, Lamin B1, and Lamin B2 in cell lines and patient samples, b) to evaluate chromatin associations with the lamina and, c) to characterize chromatin organization phenomena related to lamina conformation. In this study, we used a collection of cells that model the continuum of progression in vitro as follows: RWPE (normal prostate epithelium), LNCaP (adenocarcinoma), VCaP and MDAPCa2a/b (bone metastatic). We also evaluated whether the phenotypes for lamin deposition observed in vitro correlate with that of patient samples, via immunohistochemistry of tissue microarrays. We have identified that Lamin A content is significantly lower in bone metastatic cell lines. While VCaP cells lack Lamin A deposition, MDAPCa2a cells have a heterogeneous distribution: cells that grow in contact with the cell culture surface express Lamin A while cells that grow atop 3D clusters of cells do not. In contrast, Lamin B1 and B2 content is consistent across cell lines. Analysis of tissue microarray immunohistochemistry showed congruent results to the in vitro findings: patient samples derived from higher-grade adenocarcinomas show a decreased number of lamin A positive cells.​ This endogenous lack of Lamin A in VCaP results in an altered lamin-associated domain distribution that can potentially result in abnormal heterochromatin formation, as characterized by ChIP-seq. Further,​through a comprehensive analysis of genome architecture via chromosome conformation capture, we observe a change in the radial positioning of the chromosomes when comparing cells that model normal epithelium, adenocarcinoma, and bone metastasis. Given that the primary metastatic site for prostate cancer is the bone, we evaluated the effect of bioavailable calcium on lamin expression in vitro. Interestingly, we find that in cells cultured on vessels coated in amorphous calcium phosphate, lamin expression is ablated both in normal epithelium and adenocarcinoma cell lines, independent of testosterone levels. Taken together, our results show that lamin content, and in particular loss of lamin A, could be an early predictor of disease progression potential, affecting nucleus mechanics and pliability, ultimately facilitating metastasis. Further, the altered chromatin organization dynamics can potentially act as a prelude for pro-metastatic transcription Citation Format: Rebeca San Martin, Priyojit Das, Sanaz Hossain, Rachel Patton McCord. Nuclear lamin content as a biomarker for prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A061.

VIOLET: A phase I/II trial evaluation of radioligand treatment in men with metastatic castration-resistant prostate cancer with [161Tb]Tb-PSMA-I&T.

TPS281 Background: [177Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 (177Lu). Terbium-161 (161Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown superior in-vitro and in-vivo results in comparison with 177Lu. We hypothesize that [161Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [161Tb]Tb-PSMA-I&T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [161Tb]Tb-PSMA-I&T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [161Tb]Tb-PSMA-I&T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .

A Bioreactor for 3D In Vitro Modeling of the Mechanical Stimulation of Osteocytes.

The bone is a mechanosensitive organ that is also a common metastatic site for prostate cancer. However, the mechanism by which the tumor interacts with the bone microenvironment to further promote disease progression remains to be fully understood. This is largely due to a lack of physiological yet user-friendly models that limit our ability to perform in-depth mechanistic studies. Here, we report a tunable bioreactor which facilitates the 3D culture of the osteocyte cell line, MLO-Y4, in a hydroxyapatite/tricalcium phosphate (HA/TCP) scaffold under constant fluidic shear stress and tunable hydrostatic pressure within physiological parameters. Increasing hydrostatic pressure was sufficient to induce a change in the expression of several bone remodeling genes such as Dmp1, Rankl, and Runx2. Furthermore, increased hydrostatic pressure induced the osteocytes to promote the differentiation of the murine macrophage cell line RAW264.7 toward osteoclast-like cells. These results demonstrate that the bioreactor recapitulates the mechanotransduction response of osteocytes to pressure including the measurement of their functional ability in a 3D environment. In conclusion, the bioreactor would be useful for exploring the mechanisms of osteocytes in bone health and disease.

Mechanobiological evaluation of prostate cancer metastasis to bone using an in vitro prostate cancer testbed

Prostate cancer exhibits a propensity to metastasize to the bone, which often leads to fatality. Bone metastasis is characterized by complex biochemical, morphological, pathophysiological, and genetic changes to cancer cells as they colonize at bone sites. In this study, we report the evaluation of MDA PCa2b prostate cancer cells' nanomechanical properties during the mesenchymal-to-epithelial transition (MET) and during disease progression at the metastatic site. Bone-mimetic tissue-engineered 3D nanoclay scaffolds have been used to create in vitro metastatic site for prostate cancer. A significant softening of the prostate cancer cells during MET and further softening as disease progression occurs at metastasis is also reported. The significant reduction in elastic modulus of prostate cancer cells during MET was attributed to actin reorganization and depolymerization. This study provides input towards direct nanomechanical measurements to evaluate the time evolution of cells' mechanical behavior in tumors at bone metastasis site.

Pharmacokinetics and Biodistribution of a [89Zr]Zr-DFO-MSTP2109A Anti-STEAP1 Antibody in Metastatic Castration-Resistant Prostate Cancer Patients.

A six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a newly identified target in prostate cancer. The use of radio-labeled STEAP1-targeting antibodies with positron emission tomography (PET) may allow for detection of sites of metastatic prostate cancer and may refine patient selection for antigen-directed therapies. This was a prospective study in seven patients with metastatic castration-resistant prostate cancer who had at least one archival biopsy that was STEAP1-positive by immunohistochemistry. Patients received intravenous injections of ∼185 MBq and 10 mg of [89Zr]Zr-DFO-MSTP2109A, a humanized IgG1 monoclonal antibody directed against STEAP1. PET/CT images, blood samples, and whole-body counts were monitored longitudinally in six patients. Here, we report on safety, biodistribution, pharmacokinetics, dose estimates to normal tissues, and initial tumor targeting for this group of patients. There was no significant acute or subacute toxicity. Favorable biodistribution and enhanced lesion uptake (in both bone and soft tissue) were observed on imaging using a mass of 10 mg of DFO-MSTP2109A. The best lesion discrimination was seen at the latest imaging time, a median of 6 days postadministration. Pharmacokinetics showed a median serum T1/2 β of 198 h, volume of central compartment of 3.54 L (similar to plasma volume), and clearance of 19.7 mL/h. The median biologic T1/2 for whole-body retention was 469 h. The highest mean absorbed doses to normal organs (mGy/MBq) were 1.18, 1.11, 0.78, 0.73, and 0.71 for liver, heart wall, lung, kidney, and spleen, respectively. Excellent targeting of metastatic prostate sites in both bone and soft tissue was observed, with an optimal imaging time of 6 days postadministration. The liver and heart were the normal organs that experienced the highest absorbed doses. The pharmacokinetics were similar to other antibodies without major cross-reactivity with normal tissues. A more detailed analysis of lesion targeting in a larger patient population with correlation to immunohistology and standard imaging modalities has been reported.

Uptake of the prostate-specific membrane antigen-targeted PET radiotracer 18F-DCFPyL in elastofibroma dorsi.

PET imaging using radiotracers that target prostate-specific membrane antigen (PSMA) are increasingly being used in the evaluation of men with prostate cancer (PCa). It is therefore of increasing importance for imaging specialists to recognize potential pitfalls of this novel imaging technique. In this report, we describe a series of benign elastofibroma dorsi with uptake of the PSMA-targeted PET radiotracer F-DCFPyL. We retrospectively analyzed the imaging data of 75 men with PCa who were consecutively imaged with F-DCFPyL PET/CT. Acquired images were reviewed for the presence of radiotracer uptake in the region of the scapular tip adjacent to the chest wall. Only those lesions with discrete radiotracer uptake corresponding to an area on CT with the characteristic appearance of an elastofibroma were considered positive. In total, 18/75 (24.0%) patients had evidence of at least one elastofibroma dorsi on F-DCFPyL PET/CT. Eight (44.4%) of these patients had unilateral lesions, all of which were right sided. Detected lesions had a median maximal diameter of 2.3 cm (range: 1.3-8.4 cm) and a median perpendicular thickness to the chest wall of 0.9 cm (range: 0.6-2.5 cm). The median maximum standardized uptake value of detected lesions was 1.4 (range: 1.1-2.4) and the median maximum standardized uptake value corrected to lean body mass was 1.1 (range: 0.8-1.7). This study is the first to report uptake of a PSMA-targeted PET radiotracer in elastofibroma dorsi. Radiotracer uptake in these benign lesions should not be falsely mistaken as sites of metastatic PCa.

Abstract 2067: Attacking prostate cancer with a prodrug-doped cellular Trojan horse

Abstract Prostate cancer is the second leading cause of cancer-related deaths in American men. Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. Human mesenchymal stem cells (MSCs) are excellent candidates for cell-based drug delivery since they display tropism towards cancer sites and clinical studies have demonstrated that hundreds of millions of allogeneic human MSCs can be safely administered intravenously without adverse effects in a variety of pathological settings. Furthermore, we have previously documented that MSCs can be detected in radical prostatectomy tissue from men with prostate cancer. In this proof-of-concept study, human MSCs were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) encapsulating the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug. G114-loaded MPs were successfully internalized by MSCs without impacting MSC viability, followed by sustained release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs is selectively toxic to the PSA-secreting prostate cancer cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when co-inoculated with CWR22 prostate cancer xenografts, suggesting that cell-based delivery of G114 does not compromise potency of the prodrug in vitro or in vivo. We envision that this MSC-based platform may be developed into an effective, systemic ‘Trojan Horse’ therapy for the targeted delivery of therapeutic agents to sites of metastatic prostate cancer. Citation Format: Nathaniel Brennen, Oren Levy, Edward Han, David Marc Rosen, Juliet Musabeyezu, Helia Safaee, Sudhir Ranganath, Jessica Ngai, Martina Heinelt, Sandrine Billett, Neil Bhowmick, Samuel Denmeade, Jeffrey Karp, John Isaacs. Attacking prostate cancer with a prodrug-doped cellular Trojan horse. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2067.

Abstract 5010: Osteoblasts-derived WISP-1 increases prostate cancer metastasis through VCAM-1 upregulation

Abstract The skeleton is the most common metastatic site for prostate cancer, and increases the risk of intractable bone pain. Therefore, study of the interactions between prostate cancer and the bone microenvironment is very important. Wnt-1 induced secreted protein 1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV), which plays an important role in bone formation and many cellular processes. However, the effects of WISP-1 on the prostate cancer metastasis are not clearly understood. First, we found that WISP-1 presents in osteoblast-condition medium (OB-CM), which increases prostate cancer cell migration and invasion. In addition, OBs were infected with lentivirus containing human WISP-1 shRNA which reduced OB-CM-mediated prostate cancer metastasis. We also demonstrated that OB-derived WISP-1 enhanced cell migration via vascular cell adhesion molecule 1(VCAM-1) up-regulation in prostate cancer. Transfection of cells with VCAM-1 siRNA reduced OB-CM and WISP-1-mediated cell migration. The incresing of prostate cancer cell migration by OB-derived WISP-1 is associated with FAK and p38 activation, as well as mir-126 downregulation. Pretreatment of cells with FAK and p38 inhibitors reduced WISP-1-mediated cell migration. In contrast, WISP-1-mediated migration activity was inhibited by mir-126 mimic. Over all, we characterized an important role for OB-derived WISP-1 which regulates cell migration and invasion by increasing VCAM-1 expression in human prostate cancer via the activation of FAK, p38 and downregulation of mir-126 signaling pathway. Citation Format: An-Chen Chang, Shih-Wei Wang, Chih-Hsin Tang. Osteoblasts-derived WISP-1 increases prostate cancer metastasis through VCAM-1 upregulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5010. doi:10.1158/1538-7445.AM2014-5010

Characterization of Bone Metastases from Rapid Autopsies of Prostate Cancer Patients

Bone is the most common metastatic site for prostate cancer, and osseous metastases are the leading cause of morbidity from this disease. Recent autopsy studies prove that 100% of men who die of prostate cancer have bone involvement. Understanding the biology of prostate cancer and its evolution to an incurable androgen-independent phenotype requires an understanding of the genetic and cellular alterations that lead to the seeding and proliferation of tumor foci in bone, as well as the microenvironment in which these metastases arise. No intensive studies, however, have been conducted on osseous metastatic tissues from patients with metastatic prostate cancer due to lack of access to such tissues for profiling and other research. We show, for the first time, a reproducible methodology to obtain high quality clinical tumor tissues metastatic to the bone. This technique allowed the procurement of viable metastatic tumor tissue from involved bones in 13 recent autopsies conducted at the University of Michigan and analyzed the gene expression of these tissues using real-time PCR and microarrays. We present here the discovery of nonossified bone metastases from multiple patients with advanced prostate cancer and their subsequent characterization and comparison to nonosseous metastases from the same patients. This represents a versatile and practical approach that may be employed to characterize the steps in metastasis and the phenotypic characteristics of osseous metastasis of prostate cancer and to profile RNA, DNA, and cDNA from tumor samples metastatic to the bone.

Liver as the First and Only Metastatic Site for Prostate Cancer: A Rare Presentation

Purpose: Prostate cancer most frequently metastasizes to the bone (83-98%) and the viscera (45%). Ascitis and Liver metastasis of prostate cancer without bony involvement is very rare. We report one such case. Case: A 67 year old Caucasian male with history of Stage II (T1c NO MO) prostate adenocarcinoma with Gleason score 8 S/P brachytherapy and radiation therapy 6 months previously, presented with 2 day history of right sided abdominal pain associated with nausea and vomiting. Urine output had also progressively decreased and he was found to be in acute renal failure. On examination, he had a distended abdomen and examination consistent with ascites. There was no palpable lymphadenopathy. Abdominal CT showed massive ascites, bilateral renal cysts and non obstructing renal calculi. His Liver Function tests showed Alkaline phosphatase 407 U/L, AST 865 U/L and ALT 107 U/L. Ascitic fluid cytology revealed adenocarcinoma with special immunostains consistent with his history of prostate cancer. His PSA increased from 2.6 (6 months previous) to 180 ng/ml. MRI of the abdomen showed hepatomegaly with multiple masses throughout all lobes of liver, highly suspicious for multi focal HCC. His AFP was normal. Liver biopsy revealed the diagnosis of metastatic prostate adenocarcinoma. Bone scan was negative for any metastatic disease. He was started on Lupron® injections and daily Casodex®. Discussion: Bone is the most frequent site of metastasis in prostate cancer. Bubendorf, et al. reported 25% liver metastasis in an autopsy series of 1,589 patients with hormone refractory prostate cancer. However, in most of these pts the primary tumor was larger than 8 cm and there was involvement of other organs. Pouessel, et al. reported 28 patients with prostate cancer. Six patients had liver as the first site of metastatic disease and for only one of them, liver was found to be the only metastatic site. The median time for initial diagnosis was 38 months. Conclusion: We believe the case described here is one of the very rare instances in which liver is the first and only metastatic site for prostate cancer.

Gene-modified bone marrow cell therapy for prostate cancer

There is a critical need to develop new and effective cancer therapies that target bone, the primary metastatic site for prostate cancer and other malignancies. Among the various therapeutic approaches being considered for this application, gene-modified cell-based therapies may have specific advantages. Gene-modified cell therapy uses gene transfer and cell-based technologies in a complementary fashion to chaperone appropriate gene expression cassettes to active sites of tumor growth. In this paper, we briefly review potential cell vehicles for this approach and discuss relevant gene therapy strategies for prostate cancer. We further discuss selected studies that led to the conceptual development and preclinical testing of IL-12 gene-modified bone marrow cell therapy for prostate cancer. Finally, we discuss future directions in the development of gene-modified cell therapy for metastatic prostate cancer, including the need to identify and test novel therapeutic genes such as GLIPR1.

In vitro and In vivo Molecular Evidence for Better Therapeutic Efficacy of ABT-627 and Taxotere Combination in Prostate Cancer

Bone is the key metastatic site for prostate cancer. Endothelin 1 (ET-1) produced abundantly by prostate cancer cells binds to its receptor present on bone marrow stromal cells and favors osteoblastic response during bone metastases of prostate cancer. This suggests that interrupting ET-1 interaction with its endothelin A (ET(A)) receptor could be useful for inhibiting prostate cancer bone metastasis and, as such, may enhance the therapeutic activity of docetaxel (Taxotere), the most commonly used drug for the treatment of metastatic prostate cancer. Therefore, the goal of our study was to obtain preclinical data supporting our hypothesis that the combined use of ET(A) receptor antagonist (ABT-627; Atrasentan) with Taxotere will be superior in inducing apoptosis in vitro and inhibiting tumor growth in vivo in a SCID-hu model of experimental bone metastasis induced by C4-2b prostate cancer cells. In vitro studies were done on a panel of prostate cancer cell lines to understand the molecular basis of combination therapy, and we found that the combination was more effective in the inhibition of cell viability and induction of apoptosis in LNCaP and C4-2b cells (androgen receptor positive) but not in PC-3 cells. These results were correlated with inactivation of Akt/nuclear factor-kappaB and its target genes. For in vivo studies, the therapeutic regimen was initiated when the tumor began showing signs of growth and treatment was continued for 5 weeks. Tumor volume and serum prostate-specific antigen were used as terminal index to evaluate the therapeutic advantage of combination therapy relative to a single regimen and untreated control. At termination, we found a 90% reduction in tumor volume by combination treatment relative to the untreated control group. Most importantly, the antitumor activity was associated with the down-regulation of molecular markers in tumor tissues that were similar to those observed in vitro.

Technology Insight: monoclonal antibody imaging of prostate cancer

Imaging is a critical component of diagnosis, staging and monitoring, all of which factor heavily in treatment decision-making for cancer patients. Agents, such as antibodies, can target molecules that are relatively unique to cancer cells. Prostate-specific membrane antigen (PSMA) is the most well-established, highly restricted prostate-cancer-related cell membrane antigen known. Ten years ago, the FDA approved (111)In-capromab pendetide for use in imaging soft-tissue, but not bone, sites of metastatic prostate cancer for presurgical staging or the evaluation of PSA relapse after local therapy. For presurgical patients with high-risk disease but negative bone, CT and MRI scans, capromab demonstrated the ability to identify some patients with positive nodes, thereby sparing them an unnecessary surgical procedure. But there have been no follow-up studies to indicate that high-risk patients with a negative capromab scan have a lower failure rate after surgery. In the setting of PSA relapse, capromab is compromised by its inability to sensitively image bone metastases; bone is the first site of metastatic prostate cancer in 72% of patients. The problem with imaging bone metastases is that capromab detects an antigenic site on the intracellular portion of PSMA-a site not accessible to circulating antibodies. Early results indicate that second-generation antibodies that target the extracellular domain of PSMA might provide significant benefits in the imaging of prostate cancer.

Targeting Metastatic Prostate Cancer With Radiolabeled Monoclonal Antibody J591 to the Extracellular Domain of Prostate Specific Membrane Antigen

We performed an interim analysis of imaging data collected in 2 phase I radioimmunotherapy trials to determine the ability of monoclonal antibody (mAb) J591 directed to the extracellular domain of prostate specific membrane antigen (PSMA) to target sites of known metastatic prostate cancer accurately. Patients with progressing hormone independent prostate cancer were entered in 2 phase I dose finding trials with radiolabeled mAb J591. J591 is the first mAb targeting the extracellular domain of PSMA as well as the first de-immunized (humanized) mAb to PSMA to be tested in humans. These trials were primarily designed to assess dose limiting toxicity, maximum tolerated dose, pharmacokinetics and organ dosimetry. Planar gamma camera imaging studies obtained on the first 53 patients were reviewed and compared to sites of metastatic prostate cancer visualized on conventional imaging studies including bone scan, computerized tomography and/or magnetic resonance imaging. In 1 trial 29 patients received 111indium-J591 for imaging followed by 90yttrium-J591 for therapy. In the parallel trial 24 patients were treated with 177lutetium-J591, an isotope that can be imaged directly. Of 53 patients reviewed 46 (87%) had evidence of metastatic disease on conventional scans. Overall, of the 43 evaluable patients J591 accurately targeted bone and/or soft tissue lesions in 42 (98%). J591 accurately targeted bone lesions in 32 of 34 (94%) and soft tissue lesions in 13 of 18 (72%) evaluable patients. Radiolabeled J591 accurately targets bone and soft tissue metastatic prostate cancer sites, and may be useful for targeting therapeutic and/or diagnostic imaging agents.

A 5-fluorodeoxyuridine prodrug as targeted therapy for prostate cancer

A method for targeted delivery of the cytotoxic agent 5-fluorodeoxyuridine (FudR) ( 1) to sites of metastatic prostate cancer is described. The prodrug was synthesized by coupling the active drug (FudR) to the PSA-peptide via a self-cleaving diamino acid linker to produce HSSKLQ-Leu-Aib-FudR. This prodrug serves as a substrate for prostate specific antigen (PSA). This approach permitted efficient conversion of the inactive prodrug back to the active cytotoxic state by the enzymatic activity of PSA which is highly expressed by prostate cells.

In vivo activity of a PSA-activated doxorubicin prodrug against PSA-producing human prostate cancer xenografts.

There is currently no effective therapy for men with metastatic prostate cancer who relapse after androgen ablation. Prolonged administration of effective concentrations of standard chemotherapeutic agents is usually not possible because of dose-limiting systemic toxicities. A new strategy to target cytotoxic agents specifically to sites of metastatic prostate cancer while avoiding systemic toxicity would be to develop prodrugs that are inactive when given systemically but become activated when processed proteolytically within prostate cancer metastases by prostate-specific antigen (PSA). In this study, the in vivo activity of a prodrug consisting of doxorubicin (Dox) conjugated to a PSA-specific peptide carrier is described. Nude mice bearing PSA-producing human prostate cancer xenografts were treated either intraperitoneally (IP) or by continuous infusion with the Dox prodrug. Toxicity (weight loss, death) and antitumor efficacy (tumor volume changes) were determined. The PSA-peptide Dox prodrug had no discernible systemic toxicity when given at four times the 100% lethal Dox equivalent dose. An IP dose of 60 mg/kg/week x 4 weeks resulted in a 57% decrease in tumor weight vs. control after 40 days. A 25 mg/kg/week dose given by continuous infusion produced a similar decrease in tumor weight vs. control. The PSA-specific peptide/doxorubicin prodrug can be used to deliver higher intratumoral levels of Dox for longer duration while avoiding systemic toxicity. In addition, these results validate the specificity of the PSA-specific peptide as a targetable drug carrier. This PSA-specific peptide could also be used as a carrier to target a wide variety of cytotoxic agents for specific activation within sites of metastatic prostate cancer.