Drug design strategies for the treatment of prostate cancer

Lauer, Richard C.; Friend, Sarah; Rietz, Cecilia; Pasqualini, Renata; Arap, Wadih

doi:10.1517/17460441.2015.978855

Cited by 8 publications

(4 citation statements)

References 61 publications

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“…While surgical resection of primary tumors in concert with systemic chemotherapy has provided success in the treatment of localized cancers, metastatic disease has proven remarkably resistant to modern targeted therapies, rendering these cancers incurable. Indeed, to mitigate the risk of future metastasis, many patients are subjected to highly morbid treatment regimens that negatively impact quality of life 5 . Therapies that specifically target the rate-limiting steps of metastatic dissemination of tumor cells could significantly improve cancer treatment by removing the threat of systemic disease and decreasing our dependency on systemic therapies with detrimental side-effects 1 – 4 .…”

Section: Introductionmentioning

confidence: 99%

Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis

et al. 2018

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Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.

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Section: Introductionmentioning

confidence: 99%

Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis

et al. 2018

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“…The treatment options for metastatic androgen-independent prostate cancer (20,21) are limited. The lack of clinically relevant prostate cancer models has hampered the discovery of important molecules that permit androgen independence and therefore could be used as therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

Mandelin

Cardó-Vila

Driessen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgenindependent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on these peptides and subsequent mass spectrometry revealed a receptor for the peptide PKRGFQD, α-2-macroglobulin, and for SNTRVAP, 78-kDa glucose-regulated protein (GRP78). These results indicate that GRP78 and α-2-macroglobulin are highly active in osteoblastic, androgen-independent prostate cancer in vivo. These previously unidentified ligand-receptor systems should be considered for targeted drug development against human metastatic androgen-independent prostate cancer.peptides | ligand receptors | phage display | GRP78 | tumor targeting A ndrogen deprivation remains the standard therapy for metastatic prostate cancer. Despite the favorable initial response, in most cases the disease progresses, becomes androgen-independent, and gives rise to soft tissue and osteoblastic bone metastases that ultimately lead to death (1, 2). Paradoxically, all currently available animal models of osteoblastic bone metastases are androgen dependent (3-6). The first (to our knowledge) human prostate cancer xenograft model that does not express androgen receptor but still induces a strong osteogenic response led Li et al. (7) to conclude that androgen receptor-null cells contribute to the castrate-resistant osteoblastic progression of prostate cancer and that targeting these cells will be critical in the treatment of prostate cancer bone metastases.In vivo phage display can be used to explore the surface of cells in their anatomical microenvironment (8)(9)(10)(11)(12)(13)(14). This technology enables the identification of molecular signatures that could allow targeted systemic delivery of therapeutic agents to cancer tissues (9,12,15,16). Using such methodology and the special prostate cancer model (7), we hypothesized that ligandreceptor pairs for targeting metastasizing androgen-independent prostate cancer cells could be identified.Here we select two novel ligand peptides that were selected in vivo from human androgen-independent prostate cancer xenografts. We show that they target the surface of an androgenindependent prostatic cell line in vitro and home to androgen receptor-null prostate tumors in vivo. With affinity chromatography, we next isolated their respective receptors, 78-kDa glucose-regulated protein (GRP78) and α-2-macroglobulin, from tumor lysates and as a proof of principle verified the peptide-GRP78 interaction in vitro with recombinant GRP78. These data confirm that GRP78 is a functional molecular target on prostatic cancer cell surfaces in vivo. Such ligand-receptor systems may be applicable to targeted therapy and should be...

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“…Testosterone suppression down to castration level reduces tumor development, improves symptoms and can lead to disease specific survival . For suppressing testosterone in the treatment of advanced and metastatic prostate cancer, hormone therapy with luteinizing hormone–releasing hormone (LHRH) agonists has constituted the main approach . LUP is a synthetic superagonist of the LHRH, which posses greater potency than the natural hormone.…”

Section: Introductionmentioning

confidence: 99%

“…[1] For suppressing testosterone in the treatment of advanced and metastatic prostate cancer, hormone therapy with luteinizing hormone-releasing hormone (LHRH) agonists has constituted the main approach. [2] LUP is a synthetic superagonist of the LHRH, which posses greater potency than the natural hormone. LUP desensitizes and downregulates pituitary LHRH receptors, thus reducing luteinizing hormone (LH) synthesis and release.…”

Section: Introductionmentioning

confidence: 99%

In situ forming PLGA implant for 90 days controlled release of leuprolide acetate for treatment of prostate cancer

Enayati

Mobedi

Hojjati-Emami³

et al. 2017

Polym. Adv. Technol.

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In prostate cancer, hormone therapy via leuprolide acetate drug (LUP) is used to lower the level of testosterone down to castration level to effectively control the development of prostate cancer. The objective of this study was to evaluate the effective parameters in degradation and controlled release of an injectable in situ formed polymeric implant, loaded with leuprolide acetate, in order to achieve an optimum formulation for sustained drug release for 90 days with minimum burst release. The main problem associating with such implants is their high burst release. Designing an injectable implant with sustained and minimum burst release has thus become an attractive challenge in drug delivery field. Effects of type of poly(lactic‐co‐glycolic acid) 75:25 copolymers (RG752, RG756) and addition of nano‐hydroxyapatite (HA) particles on degradation rates of the implants and release profiles were examined in vitro and in vivo in a rabbit animal model. Results showed that implants containing polymers with higher molecular weights had significantly lower weight loss and molecular weight reduction. Adding nanoparticles of hydroxyapatite into poly(lactic‐co‐glycolic acid) implants caused further reduction in degradation rates, leading to a more sustained drug release in vivo, with reduced burst release. Different conventional kinetic models were applied to drug release and degradation data. The degradation data fit well to the first‐order degradation model. Higuchi model was the best kinetic release model fitted to the experimental in vitro release data. This study led to an optimum formulation (RG756:RG752 3:1 + 5% HA) with sustained leuprolide release and testosterone suppression over a 90‐day period with significant decrease of burst release phase (50%, p < 0.001) compared with the conventional Eligard formulation. The histopathology test showed that the formulated implant had no effects of toxicity or tissue necrosis in organs of the animal model. Copyright © 2017 John Wiley & Sons, Ltd.

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Drug design strategies for the treatment of prostate cancer

Cited by 8 publications

References 61 publications

Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis

Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis

Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

In situ forming PLGA implant for 90 days controlled release of leuprolide acetate for treatment of prostate cancer

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