Biology subjects

Bicak, M.

Publications and source records attributed to Bicak, M..

3 recordsLinked to original sources

bioRxiv2022

Assessing Functional Androgen Receptor Pathway Activity in Response to Radiotherapy Using hK2-targeted PET Imaging

External beam radiotherapy (EBRT) remains a common treatment for all stages of PCa, but DNA damage induced by EBRT upregulates androgen receptor (AR) pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied if [89Zr]11B6-PET can accurately assess EBRT-induced AR activity. PCa mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue. EBRT increased AR pathway activity in LNCaP-AR tumors. EBRT increased prostate-specific [89Zr]11B6 uptake and hK2 levels in PCa-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice. Thus, [89Zr]11B6-PET specifically detects activation of AR pathway activity after EBRT in PCa. Further clinical evaluation of hK2-PET for monitoring EBRT is warranted.

cancer biology↗

bioRxiv2022

Orally active mGluR2/3 metabotropic antagonist pro-drug mimics the beneficial effects of physical exercise on neurogenesis, behavior, and exercise-related molecular pathways in an Alzheimer's disease mouse model

Modulation of physical activity represents an important intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimers disease (AD). One mechanism proposed to underlie the beneficial effect of physical exercise involves the apparent stimulation of adult hippocampal neurogenesis (AHN). BCI-838 is a pro-drug whose active metabolite BCI-632 is an antagonist at the group II metabotropic glutamate receptor (mGluR2/3). We previously demonstrated that administration of BCI-838 to a mouse model of cerebrovascular accumulation of oligomeric A{beta}E22Q (APPE693Q = "Dutch APP") reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of the Dutch APP mice. Here we show that (i) administration of BCI-838, physical exercise, or a combination of BCI-838 and physical exercise enhanced AHN in a four-month old mouse model of AD amyloid pathology (APPKM670/671NL/ PSEN1{Delta}exon9 = APP/PS1), (ii) administration of BCI-838 alone or associated with physical exercise led to stimulation of AHN and improvement in both spatial and recognition memory, (iii) significantly, the hippocampal dentate gyrus transcriptome of APP/PS1 mice following BCI-838 treatment up-regulated brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-MTOR pathway, and metabotropic glutamate receptors, and down-regulated EIF5A of ketamine-modulating mTOR activity, and finally (iv) qPCR findings validate a significantly strong association between increased BDNF levels and BCI-838 treatment. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHN, learning behavior, and anxiety in a mouse model of AD neuropathology.

neuroscience↗

bioRxiv2019

Genetic signature of prostate cancer resistant to optimized hK2 targeted alpha-particle therapy

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate specific enzyme human kallikrein 2 (hK2; KLK2). In multiple rodent models, Actinium-225 labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the current study we investigated options to enhance and optimize [225Ac]hu11B6 treatment. Firstly, we evaluated the possibility of exploiting IgG3, the immunoglobulin G (IgG) subclass with superior activation of complement and ability to mediate FC-gamma-receptor binding, for immunotherapeutically enhanced hK2 targeted alpha-radioimmunotherapy. Secondly, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted alpha therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression free survival was slightly increased with a single high activity compared to fractionated activity. Tumor free animals succumbing after treatment revealed no evidence of treatment associated toxicity. In addition to upregulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS and SCHLAP1, we also noted a significant decrease in both KLK3 (PSA) and FOLH1 (PSMA) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

cancer biology↗