Resistance to neoadjuvant therapy.
Neoadjuvant therapy usually refers to chemotherapy administered prior to definitive treatment such as surgery or radiation. In the context of prostate cancer neoadjuvant treatment can include androgen deprivation therapy (ADT) (also known as testosterone blockade). Although usually given in the context of a clinical trial, neoadjuvant ADT (nADT) may be used to reduce the size of locally advanced tumours, facilitating surgical resection. It has also been shown to decrease the rates of cancer escaping the prostate capsule into surrounding tissues, increasing negative surgical margins and lowering the frequency of lymph node metastases (spread) after a radical prostatectomy. Till now researchers have been unable to demonstrate significant improvements in overall survival with nADT. A possible explanation is due to treatment resistance. Urologist, Niall Corcoran and his team from the University of Melbourne have reviewed the medical literature to explain some of these mechanisms of resistance as well as potential biomarkers to help determine which cancers will respond to nADT and which may be resistant.
As mentioned in previous blogs prostate cancer growth is reliant on the effects of testosterone. Testosterone is largely produced in the adrenal gland and attaches to receptors (proteins) on prostate cancer cells signalling a pathway of changes within the cell to allow the cancer to grow.
Androgen deprivation therapy through several mechanisms blocks production of testosterone or binding to its receptors on cancer cells or the signalling pathway within the cells. Cancer, however, will do what it can to survive and evolve and develops mechanisms to resist the effects of testosterone blockade brought about by ADT. The following processes of resistance have been described:
Clonal Evolution
The ‘cell of origin’ has escaped normal growth controls and possesses a selective growth advantage over the parent cell population. The genetic instability of this cell predisposes it to producing mutant daughter cells upon replication. These clones may have mutations in the androgen receptors or components of the signalling pathway resulting in them resisting the effects of ADT.
Cancer Stem Cells
Similar to normal stem cells in the body that are responsible for the production and division of all the cells in the body, cancer stem cells (CSCs) may be responsible for the formation and growth of prostate cancer. While normal stem cells are strictly regulated, mutations cause CSCs to exhibit uncontrolled growth and differentiation. These cells develop ways to pump drugs out of cells, protect from cell death and extract important nutrients and oxygen from surrounding tissue to survive.
Cell persistence
As the name implies the cancer develops a way to keep CSCs that remain despite standard treatment. This allows them to survive and continue to grow and multiply once treatment ceases.
Drug tolerance
This phenomenon occurs where a drug is administered, a response is observed but is eventually followed by treatment failure. Treatment is then withdrawn and following a ‘drug holiday’ the same drug is re-administered, and the patient displays a second treatment response. This suggests that initial resistance to treatment is due to a reversible drug-tolerant state.
Castration resistance
This concept has been discussed in previous blogs but in a nutshell the cancer cells are able to find ways to bypass the blocked androgen receptors and continue to produce testosterone or emulate the effects of testosterone if the pathway wasn’t blocked.
Neoadjuvant ADT resistance
Patients who develop resistance have very specific changes to their prostate cancer cells as seen under the microscope on prostate biopsy specimens. These may include macro-nucleoli cribriform growth pattern, PTEN loss, ERG positive, and ductal adenocarcinoma differentiation.
Biomarkers to detect resistance to nADT
Snai2, which is part of the Snail family (not the mollusc) of molecules have been shown to increase growth potential of cancer cells, invasiveness, and resistance to treatments such as chemotherapy, radiation therapy, and immunotherapy. Snai2 has been detected in increased amounts in patients receiving acute ADT and may be associated with a poor prognosis.
So how do we beat cancer at its own game (prevent the development of resistance)? As with the success of castrate resistant prostate cancer treatment, the answer may lie with combination therapy. So instead of adding on or replacing one drug with another when resistance arises perhaps its best to give a combination of drugs upfront. This may include combining ADT with chemotherapy such as docetaxel or an immunotherapy drug such as ipataserib. Trials are currently underway to assess the effectiveness of these drug combinations which may have the potential to change the approach to neoadjuvant treatment for prostate cancer and improve overall survival.
Reference
Pechlivanis M, Campbell BK, Hovens CM, Corcoran NM. Biomarkers of Response to Neoadjuvant Androgen Deprivation in Localised Prostate Cancer. Cancers 2022, 14, 166.
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About the Author Kalli Spencer MBBCh, FC Urol (SA), MMed (Urol), Dip.Couns (AIPC) Kalli is an internationally renowned Urological Surgeon, specialising in oncology and robotic surgery. He trained and worked in South Africa, before relocating to Australia where he has worked at Macquarie University Hospital and Westmead Hospital. His passion for what he does extends beyond the operating room, through public health advocacy, education and community awareness of men’s health, cancer and sexuality. Kalli has been involved with the Prostate Cancer Foundation of Australia for many years, advocating for improved cancer care and facilitating community prostate cancer support groups. |
