Multiparametric MRI as a Predictor of PSA Response in Patients Undergoing Stereotactic Body Radiation Therapy for Prostate Cancer.

Purpose: To maximize the therapeutic ratio, it is important to identify adverse prognostic features in men with prostate cancer, especially among those with intermediate risk disease, which represents a heterogeneous group. These men may benefit from treatment intensification. Prior studies have shown pretreatment mpMRI may predict biochemical failure in patients with intermediate and/or high-risk prostate cancer undergoing conventionally fractionated external beam radiation therapy and/or brachytherapy.

Dosimetric feasibility of neurovascular bundle-sparing stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer to preserve erectile function.

Objective: We aim to test the hypothesis that neurovascular bundle (NVB) displacement by rectal hydrogel spacer combined with NVB delineation as an organ at risk (OAR) is a feasible method for NVB-sparing stereotactic body radiotherapy.

Methods: Thirty-five men with low- and intermediate-risk prostate cancer who underwent rectal hydrogel spacer placement and pre-, post-spacer prostate MRI studies were treated with prostate SBRT (36.25 Gy in five fractions).

Stereotactic body radiotherapy with periprostatic hydrogel spacer for localized prostate cancer: toxicity profile and early oncologic outcomes.

Background: Multiple phase I-II clinical trials have reported on the efficacy and safety of prostate stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer. However, few have reported outcomes for prostate SBRT using periprostatic hydrogel spacer (SpaceOAR; Augmenix). Herein, we report safety and efficacy outcomes from our institutional prostate SBRT experience with SpaceOAR placement.

Velocity-based Adaptive Registration and Fusion for Fractionated Stereotactic Radiosurgery Using the Small Animal Radiation Research Platform.

Purpose: To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP).

Methods And Materials: C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification.

CDKN2A/p16 Loss Implicates CDK4 as a Therapeutic Target in Imatinib-Resistant Dermatofibrosarcoma Protuberans.

Dermatofibrosarcoma protuberans (DFSP) is an aggressive PDGFB-dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences. Some DFSP progress to a higher-grade fibrosarcomatous form, with rapid growth and increased risk of metastasis. Imatinib provides clinical benefit in approximately 50% of patients with unresectable or metastatic DFSP.

The HSP90 inhibitor, AT13387, is effective against imatinib-sensitive and -resistant gastrointestinal stromal tumor models.

The majority of gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT, an HSP90 client protein. Further secondary resistance mutations within KIT limit clinical responses to tyrosine kinase inhibitors, such as imatinib. The dependence of KIT and its mutated forms on HSP90 suggests that HSP90 inhibition might be a valuable treatment option for GIST, which would be equally effective on imatinib-sensitive and -resistant clones.

14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma.

14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B).

Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.

Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRalpha (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor.

Ala657 and conserved active site residues promote fibroblast activation protein endopeptidase activity via distinct mechanisms of transition state stabilization.

Fibroblast activation protein (FAP) and dipeptidyl peptidase-4 (DPP-4) are highly homologous serine proteases of the prolyl peptidase family and therapeutic targets for cancer and diabetes, respectively. Both proteases display dipeptidyl peptidase activity, but FAP alone has endopeptidase activity. FAP Ala657, which corresponds to DPP-4 Asp663, is important for endopeptidase activity; however, its specific role remains unclear, and it is unknown whether conserved DPP-4 substrate binding residues support FAP endopeptidase activity.

Synthesis and structure-activity relationship of N-acyl-Gly-, N-acyl-Sar- and N-blocked-boroPro inhibitors of FAP, DPP4, and POP.

The structure-activity relationship of various N-acyl-Gly-, N-acyl-Sar-, and N-blocked-boroPro derivatives against three prolyl peptidases was explored. Several N-acyl-Gly- and N-blocked-boroPro compounds showed low nanomolar inhibitory activity against fibroblast activation protein (FAP) and prolyl oligopeptidase (POP) and selectivity against dipeptidyl peptidase-4 (DPP4). N-Acyl-Sar-boroPro analogs retained selectivity against DPP4 and potent POP inhibitory activity but displayed decreased FAP inhibitory activity.