Dataset Information

Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer.

ABSTRACT: Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.

SUBMITTER: McDevitt MR

PROVIDER: S-EPMC5915579 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer.

McDevitt Michael R MR Thorek Daniel L J DLJ Hashimoto Takeshi T Gondo Tatsuo T Veach Darren R DR Sharma Sai Kiran SK Kalidindi Teja Muralidhar TM Abou Diane S DS Watson Philip A PA Beattie Bradley J BJ Timmermand Oskar Vilhemsson OV Strand Sven-Erik SE Lewis Jason S JS Scardino Peter T PT Scher Howard I HI Lilja Hans H Larson Steven M SM Ulmert David D

Nature communications 20180424 1

Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the ...[more]

PMID: 29691406

Similar Datasets

Project description:In this study, we present an intensity-modulated radiotherapy technique based on forward planning dose calculations to provide a concave dose distribution to the prostate and seminal vesicles by means of modified dynamic arc therapy (M-DAT). Dynamic arcs (350 degrees) conforming to the beam's eye view of the prostate and seminal vesicles while shielding the rectum, combined with two lateral oblique conformal fields (15 degrees with respect to laterals) fitting the prostate only,were applied to deliver doses of 78 Gy and 61.23 Gy in 39 fractions to the prostate and seminal vesicles respectively. Dynamic wedges (45 degrees of thick end, anteriorly oriented) were used with conformal beams to adjust the dose homogeneity to the prostate, although in some cases, hard wedges (30 degrees of thick part,inferiorly oriented) were used with arcs to adjust the dose coverage to the seminal vesicles. The M-DAT was applied to 10 patients in supine and 10 patients in prone positioning to determine the proper patient positioning for optimum protection of the rectum. The M-DAT was compared with the simplified intensity-modulated arc therapy (SIMAT) technique, composed of three phases of bilateral dynamic arcs. The mean rectal dose in M-DAT for prone patients was 22.5 +/- 5.1 Gy; in M-DAT and SIMAT for supine patients, it was 30.2 +/- 5.1 Gy and 39.4 +/- 6.0 Gy respectively. The doses to 15%, 25%, 35%, and 50% of the rectum volume in M-DAT for prone patients were 44.5 +/- 10.2 Gy, 33.0 +/- 8.2 Gy, 25.3 +/- 6.4 Gy, and 16.3 +/- 5.6 Gy respectively. These values were lower than those in M-DAT and in SIMAT for supine patients by 7.7%, 18.2%, 22.4%, and 28.5% and by 25.0%, 32.1%, 34.9%, and 41.9% of the prescribed dose (78 Gy) respectively. Ion chamber measurements showed good agreement of the calculated and measured isocentric dose (maximum deviation of 3.5%). Accuracy of the dose distribution calculation was evaluated by film dosimetry using a gamma index, allowing 3% dose variation and 4 mm distance to agreement as the individual acceptance criteria in prostate and seminal vesicle levels alike for all supine and prone patients. We found that fewer than 10% of the pixels in the dose distribution of the calculated area of10 x 10-cm failed the acceptance criteria. These pixels were observed mainly in the low-dose regions, particularly at the level of the seminal vesicles. In conclusion, the single-phase M-DAT technique with patients in the prone position was found to provide the intended coverage of the prescribed doses to the prostate and seminal vesicles with improved protection for the rectum. Accordingly, M-DAT has replaced non-modulated conformal radiotherapy or SIMAT as the standard treatment for prostate cancer in our department.

Dataset Information

Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer.

Publications

Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets