HomeENGLISH MAGAZINECancers handling the weight of gender: how anti-androgens enhance targeted-therapy and immunity

Cancers handling the weight of gender: how anti-androgens enhance targeted-therapy and immunity

The androgen receptor (AR-alpha) is a type of nuclear receptor activated by the male sex hormone testosterone. Females have lower levels of androgens, including testosterone, while estrogen is the main mover or their biology. An influence of steroid hormones in cancer has been known for decades now, in addition to their role in reproductive cancers (e.g. breast cancer, ovarian cancer and testicular seminoma). Researchers at the University of Texas MD Anderson Cancer Center demonstrated that AR signaling affects the response to BRAF / MEK inhibitor therapy in both males and females with melanoma. This research confirms the impact of biological sex on the response to BRAF / MEK targeted therapy and shows for the first time that these inhibitors increase AR-alpha signaling, leading to therapeutic resistance and poor response to treatment. The findings provide a new focus for combating therapeutic resistance and a possible answer to why men face a worse prognosis than women when melanoma is diagnosed.

It has already been shown in preclinical models of melanoma that AR-alpha blockade improved the response to BRAF / MEK targeted therapy in both males and females. The study began with an observation from a neoadjuvant clinical trial for BRAF / MEK inhibitors in stage III melanoma (NCT02231775) in which female patients had a higher rate of major pathological response (MPR, defined as <10 % viable tumor at time of surgery) relapse-free survival rates and rates compared to male patients. To validate these findings, the group studied other patients with locally advanced metastatic melanoma, including 51 patients treated with neoadjuvant BRAF / MEK inhibitors (30 female and 21 male). The MMR rate was 66% for females and 14% for males, and the two-year RFS rate was 64% for females and 32% for males. After excluding other possible factors contributing to MPR (including performance status, body mass index, disease stage, and mutation status), the research team validated sexual dimorphism in several other cohorts.

The analysis included a total of 664 patients who received BRAF and / or MEK targeted therapy for stage III or IV melanoma. In multiple studies, the researchers found a trend towards better progression-free survival and overall survival in females than males. Longitudinal evaluation of the available tissue samples revealed significantly higher levels of AR-alpha in male patients during treatment compared to baseline and significantly higher levels of AR during treatment in male and female patients whose cancer did not respond to the combination of therapy. targeted. In collaboration with MD Anderson’s Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, the researchers validated their observational results in several preclinical models. First, they showed that female mice implanted with melanoma tumors respond better than male mice to BRAF/MEK inhibitors. When all mice were given testosterone, tumor progression and resistance to treatment occurred in both sexes.

Finally, when mice were given an AR inhibitor plus targeted therapy, responses to melanoma treatment improved in both sexes. Recent research has shown that AR-mediated resistance can impact other cancers and types of treatment. Current findings underscore the need to better understand the impact of hormone therapy during BRAF and / or MEK inhibitor therapy for melanoma and other cancers. Therefore, given that the potentiating effect on BRAF/MEK inhibitors is practically comparable for men and women, it is speculative that the action of AR-alpha is not to be referred to a dimorphic effect, that is, linked specifically to sex. The suppressive effect of testosterone on some aspects of the immune system has been well known for a long time; since inhibiting AR-alpha can also enhance the effects of checkpoint therapy, the cellular signaling of this receptor certainly has a cellular reinforcement action on the proliferation of malignant melanoma cells and “immunological” hindering against them.

Even regardless of the presence of prostate cancer in men or gynecological cancer in women, AR-alpha inhibitors such as bicalutamide or enzalutamide are very well tolerated and may very well find use as safe enhancers of targeted therapy in resistant melanoma. chemotherapy or checkpoint inhibitors.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.

Scientific references

Vellano CP et al., Wargo J. Nature 2022 Jun 15.

Pala L et al. Cancer Cell. 2022; 40(5):455-457.

Ma M et al. J Exp Med. 2021; 218(2):e20201137. 

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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