Male hormones, used many years ago and then abandoned (due to their excessive side effects), are now being used once again in a study carried out by Australian researchers.
This approach, which is both old and new, could be a major breakthrough in the treatment of oestrogen-sensitive breast cancers, which account for two-thirds of all breast carcinomas.
So, what’s the story?
Oncologists, always on the lookout for more effective therapies, are focusing their attention on androgens, i.e. male hormones (and testosterone, in particular) that are also found in the female body, albeit in low concentrations.
These hormones are the natural antagonists of oestrogen (which feeds the growth of cancer cells). Therefore, it is thought that activating them could block the cancer and especially metastases (contrary to what happens with prostate cancer, where instead it is the androgens that stimulate the cancerous cells).
In the case of the breast, the idea of using androgens actually dates back several years. When oncologists realised that many forms of breast cancer were boosted by female sex hormones, they immediately thought of counteracting their growth by administering male ones.
However, at that time, knowledge of how hormone circuits work was still inadequate. Little was known about the relationship between different types of hormones and the “structures” (receptors) of cancer cells with which hormones interact.
In addition, the only molecules available for use in therapies were the hormones themselves (in particular, testosterone, and not – as is now the case – more selective androgenic drugs), which caused serious side effects such as masculinization (possible growth of a beard and body hair, changes to the voice, hair loss, and others).
Hence, this approach was soon abandoned and considered impractical, partly because in the meantime effective alternative therapies to block oestrogen had been developed, using specially-developed molecules. But, since a number of women did not respond effectively to these therapies, the idea of “recovering” androgens was again considered, partly because knowledge of what happens to the breast in both healthy and cancerous conditions had increased considerably.
Researchers at the University of Adelaide (Australia) therefore decided to stimulate the androgen receptors found on cancer cells using different types of substances similar to testosterone but much more “targeted”. They were able to demonstrate – on cell cultures and on models (organoids) obtained by multiplying the cells of sick women – that the cancer cells died.
But how does the activation of androgen receptors using specific therapies lead to the “suppression” of cancer cells?
The biological mechanisms are very complex, but we can try to explain them very briefly as follows: the “enhancement” of androgen receptors causes a consequent disorder of the DNA traits (the genetic code) that govern the oestrogen receptors, which cancer cells need in order to grow, and all this makes the latter receptors much less effective.
“These findings,” the Australian oncologists write in Nature Medicine, “provide compelling evidence that the androgen receptor plays a suppressing role in oestrogen-sensitive breast cancer and offers a therapeutic opportunity”.
Furthermore, this technique appears to be able to overcome the resistance that some forms of cancer show towards widely–used anti-cancer drugs to treat breast cancer, such as tamoxifen or the so-called anti-cyclin CDK4/6, with fewer side effects.
And lastly, the substances used by the Australian researchers have been shown to increase bone density.
The results of these laboratory studies will soon be transferred directly to patients: in the second quarter of this year, in fact, a phase 3 trial (the one preceding final approval) with Enobosarm, an agent that activates the androgen receptor, will begin in patients with metastatic oestrogen receptor and androgen receptor positive breast cancer, who are resistant to traditional forms of endocrine therapy. The phase 2 trial, which ended a few months ago, has shown positive results, and testing will now begin in a larger number of patients.