How Prostate Cancer Becomes Resistant To Treatment

Resistance to treatment comes in different forms. It is a proven fact in many diseases and a variety of treatments.

One of the classic examples of treatment resistance is antibiotic resistance. When you use antibiotics too much, or if you don’t actually require them, bacteria end up creating defenses against the antibiotic.

Thus, that particular substance will no longer kill bacteria in the future, and you need to use a new antibiotic.

In prostate cancer, resistance to treatment doesn’t work the exact same way, but the basics are similar. When prostate cancer becomes resistant to treatment, doctors need to look for new alternatives. Luckily, there are different ways to treat prostate cancer, and the most important resistance is against androgen deprivation therapy.

When we talk about treatment-resistant cancer, we usually refer to resistance to hormone therapy. That’s why in this article, we’re talking about treatment-resistant prostate cancer, also known as castrate-resistant prostate cancer.

How does resistance work in this case? How do you know that prostate cancer is resistant to hormone therapy? And what can doctors do in that case?

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Hormones and prostate cancer

Hormone therapy for prostate cancer is also known as androgen deprivation therapy. This therapy’s rationale is that prostate cancer uses testosterone to trigger more rapid growth of the tumor. Thus, by cutting out the supply of testosterone in the prostate, we would halt disease progression.

Hormone therapy uses androgen suppressors. The resulting levels of testosterone would be compatible with those found in people who had their testicles removed. That’s why we can see the term “chemical castration” as an alternative way to refer to this treatment.

Castrating prostate cancer can be helpful to slow down the advance of the disease. It is an excellent therapy for advanced cases. It does not cure cancer or destroy cancer cells. Instead, what it does is reducing the number of tools cancer has to keep on growing.

The main goal is preventing metastatic prostate cancer and the spread of cancer cells to other organs. Still, if your prostate cancer becomes castrate-resistant, there are different ways to treat your condition. Chemotherapy, radiation therapy, and other treatments are still available. They are not less effective in castrate-resistant cancer.

What is the link between testosterone and prostate cancer?

Testosterone has many roles in the organism, depending on each tissue. When it converts into DHT, testosterone is more active still and triggers new functions. That is what happens during puberty. After increasing their circulating levels of DHT, children start to experience changes.

The voice deepens, body hair starts to show up, the external genitalia grows, and the prostate increases its size, too. So, you could say that testosterone increases the size of the prostate after it turns into DHT.

In most cases, the prostate stays the same regardless of any change in testosterone levels. But sometimes, there’s an increase in DHT inside the prostate. We can also have the same DHT level in a very sensitive prostate. In both cases, the prostate would start to grow more rapidly.

DHT levels in the prostate depend on the microenvironment of the prostate. Sometimes we have normal levels of testosterone in the body but high levels in the prostate. The opposite can be true, and we can have high circulating levels and normal levels in the prostate. They are different environments, and we shouldn’t extrapolate the results of a blood test.

On the other hand, the prostate can be more or less sensitive to testosterone. It all depends on the number of androgen receptors in prostate cells. A higher number of androgen receptors would sensitize the prostate to androgen signaling. Thus, even low DHT levels in the prostate would trigger accelerated growth.

The number of androgen receptors can change in response to different stimuli. The most common is the concentration of testosterone in the body. Thus, if we have low testosterone levels, the prostate increases the number of androgen receptors to compensate. Maintaining normal levels of testosterone when we are young would prevent this from happening (1).

How does hormone treatment work in prostate cancer?

Hormone treatment for cancer is not usually recommended in an early stage. Most cases of prostate cancer are diagnosed early when they are still inside the prostate capsule. This is localized prostate cancer, and many cases are slow-growing.

Then, surgery and radiotherapy are enough to take care of cancer in these cases. Sometimes doctors recommend active surveillance instead of aggressive treatment.

Doctors usually recommend hormone treatment in these cases (1):

  • When prostate cancer comes back, it can be a new tumor or chemical recurrence of prostate cancer.

  • When prostate cancer is starting to spread, in these cases, hormone treatment slows down metastasis and shrinks the tumor.

  • To shrink tumors before surgery. In these cases, we’re usually talking about a massive tumor in the prostate gland.

After starting androgen deprivation therapy, our circulating levels of testosterone begin to drop. This causes a temporary restriction of prostate growth. The gland no longer has the stimuli for accelerated growth. Thus, the tumor may even start to shrink. 

In most cases, hormone therapy is effective in preventing urinary obstruction and other symptoms. They start causing problems when the prostate is too big. This compromises the flow of urine that goes through the urethra, and a significant volume of urine stays in the bladder.

But androgen deprivation therapy is only a temporary measure. After some time, the prostate becomes resistant to this therapy. The number of androgen receptors increases and the gland starts to grow once again. Regardless of the testosterone levels, the gland keeps growing, and we don’t fully know why. That is when we talk about castrate-resistant prostate cancer (1, 2).

How does cancer become resistant to hormone therapy?

Cancer progression is much more than growing the tumor and metastasis. It involves thousands of processes inside the cell. It all starts with a few mutations to the DNA of a previously normal cell. This cell loses its restraint and starts to divide without limit. That’s only the early start of cancer. 

New cancer cells born programmed to divide rapidly. This rapid division is also disorganized and fosters new DNA mutations. As the DNA continues to mutate, the cell loses its normal functions and looks different from healthy cells. More and more functions are lost or replaced by others, and cancer becomes more aggressive.

Androgen activation and response to testosterone could be one of the functions affected by new DNA mutations. Thus, the resulting cancer cell does not depend on androgens to keep growing. Reducing levels of testosterone, in this case, would not trigger a significant change in growth speed. In other cases, lower testosterone levels are met by an increase of androgen receptors in cancer cells.

Either way, androgen deprivation stops working after a while, and in some cases, it may not work from day one. This is what we call castrate-resistant cancer (3, 4).

The exact genes and metabolism changes that turn cells into castrate-resistant cancer are still elusive. However, recent studies have shown specific changes in metabolism and genetics.

What the research says

For example, researchers performed a study on a subtype of treatment-resistant cancer – neuroendocrine prostate cancer. This is one of the most aggressive types of treatment-resistant cancer.

The investigators found these changes in neuroendocrine prostate cancer (3, 4):

  • There is a downregulation of a tumor suppressor gene known as protein kinase C lambda/iota. This type of gene normally prevents the transformation of healthy cells into cancer.

  • There’s a signaling system inside the cell that is upregulated. It is what we call mTORC1/ATF4. 

  • This signaling system triggers an increase in serine. This is a non-essential amino acid and a metabolite in prostate cancer.

  • There’s an increase in the expression of an enzyme. It is phosphoglycerate dehydrogenase.

Together, these changes turn prostate cancer into a very aggressive type, resistant to hormone therapy. It is usually not possible to pinpoint the exact triggers and alterations in each patient. However, we can use this data to create new targeted therapies for aggressive and resistant cancer.

For example, new investigation lines try to find a drug that blocks phosphoglycerate dehydrogenase in neuroendocrine prostate cancer. Other researchers are trying to find a way to stop serine production without causing toxicity. So, there are alternatives, even in castrate-resistant cancer (5).

Diagnosing castrate-resistant cancer

Castration resistant prostate cancer (CRPC) is a type of advanced prostate cancer. We won’t expect to find this type of cancer in patients who are still in an early phase. But if doctors treat a patient who requires hormone therapy, it would be useful to know how sensitive it will be to this therapy.

Is there a way to diagnose castration resistant prostate cancer?

Cancer is so unpredictable that the only way to diagnose castration resistant prostate cancer is by trial and error. It’s similar to chemotherapy, in which we don’t know how cancer cells will react until we actually see test results. In hormone therapy, doctors would start treatment, measure testosterone’s blood levels, and see what happens. 

Castration-Resistant Prostate Cancer or CRPC will be diagnosed if (6):

  • Androgen deprivation therapy is ongoing

  • Serum testosterone levels are lower than 50 ng/dL

  • The disease continues to progress as measured by tumor size, PSA level, or clinical features

To understand how it goes, we can use an example:

In this example, we have a patient who was caught off guard. He detected cancer when it was already in an advanced stage. It was spreading through lymph nodes with no signs of metastatic disease. Androgen deprivation therapy is recommended to prevent spread to the bone, lungs, or brain.

The patient starts androgen deprivation therapy and reaches testosterone levels of 39 ng/dL. After some time, they detect a metastasis nodule, and the tumor is a bit larger. Androgen deprivation therapy is clearly not useful, and cancer is resistant to hormone therapy.

Treating castrate-resistant cancer

Based on recent discoveries about how castration resistant prostate cancer works, doctors have adopted several therapeutic modalities to improve these patients’ outlook. We can still use some chemotherapy agents, immunotherapy, hormonal agents, immunotherapy, and other modalities.

More experimental drugs are currently under development.

The most common groups of drugs include (7,8):

New generation hormonal therapies

These therapeutic options arise after understanding that serum testosterone does not necessarily extrapolate to the prostate. We can have low levels of testosterone in the blood and higher levels of intraprostatic androgen levels. Thus, castration resistant prostate cancer is not always caused by androgen independence. It is sometimes caused by a different response from the prostate tissue to the available androgens. These new hormonal therapy agents interfere with new androgen receptor pathways that form in castration resistant prostate cancer. Others inhibit enzymes that block androgen synthesis. Abiraterone is perhaps one of the most important members of this group. It inhibits an enzyme called CYP17A1. By doing so, it blocks testosterone synthesis.

Androgen Receptor Inhibitors

These agents are useful in patients who increase the number of androgen receptors. They bind to androgen receptors and leave testosterone out of the equation. Since they do not trigger any cell response, they silence androgen receptors. One of the best examples is enzalutamide.

Cytotoxic chemotherapy

We can still use chemotherapy in these patients, but we need to know which agents work best. Doctors typically use docetaxel therapy or cabazitaxel. They are both taxanes. They promote a disordered assembly of microtubules in the cell during the cell cycle. A conglomerate of microtubules is created and causes cell apoptosis. Docetaxel chemotherapy is the first choice, but some patients are resistant to this agent. When that happens, they can use cabazitaxel.

Bone targeting agents

In metastatic castration resistant prostate cancer (MCRPC patients), it is also essential to treat the bone tissue. Patients with skeletal-related events reduce their quality of life. They often have an additional health burden because androgen deprivation can trigger osteoporosis. Bone metastases can also break down and destroy bone tissue. Thus, healthcare providers recommend a series of agents in these patients-for example, zoledronic acid, denosumab, and radium-223 dichloride.

Cell migration targeting agents

These agents prevent metastasis in nonmetastatic CRPC (NMCRPC patients). They are very complex agents and deal with different signaling processes inside the cell. Cabozantinib and Dasatinib are two examples. They are usually combined with docetaxel and prednisone.

Immunotherapy

They are agents that induce an anti-tumor response by the immune system. There are different types of immunotherapy agents. For example, we have PROSTVAC-VF, which is a recombinant vaccine that stimulates the immune system. There is also a monoclonal antibody known as Ipilimumab.

With the list above, doctors can make a combination depending on what the patient needs. Currently approved treatments and combinations for CRPC include (8,9):

Abiraterone acetate

As noted above, it inhibits CYP17A1 enzymes. The mechanism is somewhat similar to ketoconazole but ten times greater. Studies found it very useful to increase life expectancy in cases of CRPC.

Docetaxel plus prednisone

Docetaxel was one of the first therapeutics with known effectivity against CRPC. Before this treatment, patients used to live up to 12 months. According to clinical trials, this treatment increased the overall survival and quality of life.

Cabazitaxel

It is used instead of docetaxel in castration resistant prostate cancer patients who are resistant to this treatment. Castration resistant prostate cancer comes from a pump in the cell membrane that takes out the drug, reducing its concentration inside the cell. But cabazitaxel won’t be detected by this pump. Thus, it will remain active and continue causing apoptosis in prostate cancer cells.

Sipuleucel-T

This is historically the first immunotherapy agent approved for cancer treatment. It works as a vaccine that stimulates T-cells against a particle found in cancer cells. It detects prostatic acid phosphatase and attacks cells that display this substance in the cell membrane.

As you can see, there are many treatment options. However, sometimes they won’t be enough because the cancer has advanced and is very aggressive. In these cases, the prognosis is very poor, and it is better to start a palliative treatment. This type of therapy deals with the consequences of cancer only. The main goal is to improve the quality of life without an aggressive curative approach.

Conclusion

Prostate cancer progresses as cancer cells get new DNA mutations. After a while, the tumor looks and behaves differently from healthy prostate tissue.

Testosterone sometimes stimulates a normal prostate gland to grow. This can turn into a problem in advanced prostate cancer. Thus, androgen deprivation therapy (ADT) is useful to reduce the growth rate and the chance of metastasis.

But other mutations and particular adaptations in prostate cancer cause resistance to androgen deprivation therapy. For example, cells may create more androgen receptors to compensate for the reduction of testosterone. Sometimes they become entirely independent of androgens to keep on dividing. Either way, most cases of castrate-resistant prostate cancer are aggressive and have a poor prognosis.

Still, it is possible to treat this type of cancer with a combination of agents. For example, we can use new generation hormone therapy. They use alternative ways to maximize the results of traditional hormone therapy. 

Next Up

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Sources

  1. Yassin, A., AlRumaihi, K., Alzubaidi, R., Alkadhi, S., & Al Ansari, A. (2019). Testosterone, testosterone therapy, and prostate cancer. The Aging Male, 22(4), 219-227.
  2. Rodriguez, K. M., Pastuszak, A. W., & Khera, M. (2018). The role of testosterone therapy in the setting of prostate cancer. Current urology reports, 19(8), 67.
  3. Attar, R. M., Takimoto, C. H., & Gottardis, M. M. (2009). Castration-resistant prostate cancer: locking up the molecular escape routes. Clinical Cancer Research, 15(10), 3251-3255.
  4. Sridhar, S. S., Freedland, S. J., Gleave, M. E., Higano, C., Mulders, P., Parker, C., … & Saad, F. (2014). Castration-resistant prostate cancer: from new pathophysiology to new treatment. European urology, 65(2), 289-299.
  5. Reina-Campos, M., Linares, J. F., Duran, A., Cordes, T., L’Hermitte, A., Badur, M. G., … & Diaz-Meco, M. T. (2019). Increased serine and one-carbon pathway metabolism by PKCλ/ι deficiency promotes neuroendocrine prostate cancer. Cancer Cell, 35(3), 385-400.
  6. Kamoto, T. (2014). Evaluation and diagnosis for castration resistant prostate cancer: CRPC. Nihon rinsho. Japanese journal of clinical medicine, 72(12), 2103-2107.
  7. Loriot, Y., Supiot, S., Beauval, J. B., Schlürmann, F., Pasticier, G., Sargos, P., … & Borchiellini, D. (2018). Management of non-metastatic castrate-resistant prostate cancer: A systematic review. Cancer treatment reviews, 70, 223-231.
  8. Nuhn, P., De Bono, J. S., Fizazi, K., Freedland, S. J., Grilli, M., Kantoff, P. W., … & Antonarakis, E. S. (2019). Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. European urology, 75(1), 88-99.
  9. Brave, M., Weinstock, C., Brewer, J. R., Chi, D. C., Suzman, D. L., Cheng, J., … & Beaver, J. A. (2020). An FDA Review of Drug Development in Non-Metastatic Castration-Resistant Prostate Cancer. Clinical Cancer Research.
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Dr Alberto Parra

Dr. Alberto Parra is a Medical Doctor and clinical researcher with extensive experience in diagnostic imaging and sports medicine. He's also interested in nutrition, fitness and family medicine, with expertise and continuing education on preventive healthcare and evidence-based medicine. He provides consultancy services to a number of individuals and entities who require medical validation of their protocols, products, supplements, and medical contents.

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