Anti-Androgen Therapy Radiosensitizes Androgen Receptor Positive Cancers to F-18 Fluorodeoxyglucose.
Indulekha SingaraveluHenry SpitzMary MahoneyZhongyun DongNalinikanth KotagiriPublished in: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (2021)
Background: A subset (35%) of triple negative breast cancers (TNBC) express androgen receptor (AR) activity. However, clinical trials with anti-androgen drugs have shown limited efficacy with about a 19% clinical benefit rate. We investigate the therapeutic enhancement of anti-androgens as radiosensitizers in combination with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) in TNBC. Methods: We screened five candidate drugs to evaluate shared toxicity when combined with either 18F-FDG, X-ray or ultraviolet (UV) radiation, at doses below their respective sub-IC50 values. Cytotoxic enhancement of anti-androgen in combination with 18F-FDG was evaluated using cell proliferation and DNA damage assays. Finally, therapeutic efficacy of the combination treatment was evaluated in mouse tumor models of TNBC and prostate cancer. Results: Bicalutamide (Bical), an anti-androgen drug, was identified to share similar toxicity in combination with either 18F-FDG or X-rays, indicating its sensitivity as a radiosensitizer to 18F-FDG. Cell proliferation assays demonstrated selective toxicity of combination Bical-18F-FDG in AR-positive 22RV1 and MDA-MB-231 cells in comparison to AR-negative PC3 cells. Quantitative DNA damage and cell cycle arrest assays further confirmed radiation induced damage to cells suggesting the role of Bical as a radiosensitizer to 18F-FDG-mediated radiation damage. Animal studies in MDA-MB-231, 22RV1 and PC3 mouse tumor models demonstrated significant attenuation of tumor growth through combination of Bical and 18F-FDG in the AR-positive model in comparison to the AR-negative model. Histopathology corroborated the in vitro and in vivo data and confirmed the absence of off-target toxicity to vital organs. Conclusion: These data provide evidence that 18F-FDG in conjunction with anti-androgens serving as radiosensitizers has utility as a radiotherapeutic agent in the ablation of AR-positive cancers.
Keyphrases
- positron emission tomography
- pet ct
- pet imaging
- cell cycle arrest
- oxidative stress
- dna damage
- computed tomography
- radiation induced
- cell proliferation
- prostate cancer
- cell death
- pi k akt
- induced apoptosis
- clinical trial
- mycobacterium tuberculosis
- high throughput
- emergency department
- radiation therapy
- high resolution
- magnetic resonance imaging
- dna repair
- cell cycle
- deep learning
- big data
- magnetic resonance
- stem cells
- bone marrow
- skeletal muscle
- machine learning
- blood glucose
- electronic health record
- combination therapy
- atrial fibrillation
- open label
- randomized controlled trial
- artificial intelligence
- phase ii
- breast cancer cells
- contrast enhanced