When Treatment Stops Working:  Blame Resistance

In the upside down world of prostate cancer, the good guys want to win the war and the bad guys are leading the resistance.

Imagine Rick’s Café in Casablanca, except it’s the bad guys, with a nod from Humphrey Bogart, who are the ones singing “La Marseillaise” – drowning out the song of the good guys with the German accents.   Upside down, indeed.

In prostate cancer, resistance is bad.  Resistance can be lethal.

Our goal is to figure out how to shut down prostate cancer’s resistance once and for all.

It’s a matter of evolution.  In the beginning, when they are very young, cancer cells aren’t that different from normal cells.  They have fairly well-defined borders, they gather in orderly groups, their growth is fairly restrained, and as cancer cells go, they’re tame.  If a normal cell looks like a clean-cut soldier, then early cancer cells look pretty much the same.  Maybe the soldier has five o’clock shadow; maybe his uniform is missing a button, maybe his boots are a little scuffed, but he’s still basically presentable.  Some cancer cells don’t ever go beyond this point.  Those are the Gleason 3 + 3 or 3 + 4 cells, the ones that tend to stay in the prostate.

Some cancer cells aren’t content to do this.  “Cancer cells are programmed to be dissatisfied with the way they are,” says medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation.  Prone to instability, fueled by bad diet, bad genes, bad lifestyle, or a bad combination of both, they evolve.  That soldier starts to look less tidy and more like Jack Nicholson’s character in The Shining, unshaven, wild-eyed, and increasingly creepy.  As cancer cells morph to become sophisticated enough to move beyond the prostate, they learn evasive maneuvers.  Block them to the right, they go to the left.  Block them from the top, and they go down.  Try to kill them, and sometimes they fake their own death.  “They hibernate for months, like a bear,” says Simons; this is called tumor dormancy.

Advanced cancer cells are like the velociraptors in Jurassic Park, constantly testing the electric fences, looking for points of weakness.  They keep getting more resistant, and more dangerous.

Resistance puts the “evil” in evolution. “Cancers experiment with their genetic code,” Simons adds, “and if you apply selective pressure,” in the form of a drug, “that’s a new challenge for them.  Part of what we’re trying to do with precision oncology is put these cells in a headlock that’s tighter and more precise.”  In response to treatment, advanced prostate cancer cells “either evolve, adapt and thrive, or they die off and become extinct.  The reason why metastatic cancer kills people is that there’s no extinction event for something that is just sitting there evolving differently than a normal cell.”

So that’s the goal, to create an extinction event.  If you think of cancer cells as dinosaurs, then what we’re looking for is the meteor that ends them once and for all.

How do we treat metastasis

* Most doctors start with androgen deprivation therapy (ADT).  Note: This is different from the limited course of ADT given to some men with radiation therapy, which is very effective. 

Long-term continuous ADT should not be started until you have actual, visible metastases,” cautions Vanderbilt University Medical Center oncologist Alicia Morgans, M.D.  “There is no scientific proof showing a benefit to starting it just because you have a rising PSA.”  

ADT causes some cells – the ones most responsive to male hormones – to become extinct.  But others just hunker down and hibernate.  “Each treatment for metastatic cancer can extend life and put the cancer back into remission,” says Simons. “But most remissions don’t last forever.”  Why not?  Because of those sleeper cells; which are quietly evolving even as they’re playing dead.

* Androgen receptor blockers.  If a man’s PSA starts to rise after he’s been on ADT for months or years, treatment moves to a new target: the androgen receptor.  Enzalutamide and abiraterone are examples of drugs that affect the androgen receptor. Abiraterone, for example, blocks the supply of testosterone inside the prostate cancer cell that the androgen receptor uses to switch on genes that say, “cancer cells , keep on dividing.”  Because some cancers evolve faster than others, some men do very well on these drugs.  But other men, even before treatment, develop androgen receptor mutations and have either a very short remission with these drugs or none at all.  Why is this?  Receptors are like electrical outlets in the wall, designed for particular chemical plugs.  It turns out that androgen receptors have two important parts.  Basically, Simons explains, “they have a North Pole and a South Pole.”  When a man with a variant, or mutated, androgen receptor takes enzalutamide or abiraterone, the drug “plugs in” to the North Pole of the androgen receptor and shuts it down, “but the South Pole keeps right on working, turning on bad genes.  We need to fund research to shut down the South Pole of the androgen receptor.”

What happens if enzalutamide or abiraterone either stop working or don’t work at all?  We move on to an ever-improving group of approaches, including:

* Chemotherapy.  Chemotherapy has traditionally been started after ADT has failed.  But doctors are seeing better results by starting these drugs while ADT is still working; a UK-led clinical trial, called STAMPEDE, found that adding the chemotherapy drug docetaxel to ADT extended survival by an average of 10 months in men who were newly diagnosed with advanced prostate cancer.  A U.S. study, CHAARTED, did something similar, giving men either ADT alone or ADT plus docetaxel, and found “significantly superior” results in the men who received the chemo with the ADT.   But could chemotherapy achieve good results by itself, before hormonal therapy?  “Precision oncology research should help answer this question and is being funded by PCF now,” says Simons. “Men who are diagnosed with metastatic prostate cancer should ask their oncologist if they should be offered the option to receive docetaxel chemotherapy upfront, before the start of hormonal therapy.”

* Targeted drugs. There are a few of these, and new compounds are being developed as we speak, in research funded by the PCF.  Two of these are olaparib and rucaparib, approved by the FDA to treat ovarian cancer.  The target of these drugs is pretty darn specific – a mutated BRCA gene that is supposed to repair damage to DNA.  Some men with prostate cancer have responded so well, Simons refers to them as “Lazarus patients.”  These are men with advanced metastatic disease, “with PSAs in the thousands, whose tumors are melting away.”  Mutated BRCA genes are the cause of breast cancer and other cancers, including prostate cancer, and they can be inherited.  Note: If cancer runs in your family, you should talk to your doctor about taking the new Cascade Genetic Test, a blood test that looks for 16 inherited genes found in different types of cancer; all of these genes are involved in DNA damage repair.

How do they work?  Olaparib and rucaparib are PARP-inhibitors.  PARP is not a gene, but a protein that helps damaged cells repair themselves.  Cancers that spring from a damaged BRCA gene selectively use PARP as their repairman of choice.  Without PARP to keep up the maintenance, the cancer cells die.

These drugs are just the beginning.  A bunch of genes involved in prostate cancer might make very effective targets – which means that if a genetic test shows that you have a mutated gene, there may be a medicine coming soon that will target that particular one.

“To have a cancer extinction event, to cure men with advanced prostate cancer, we have to change the environment for the cancer cells,” says Simons.  “Our new cancer medications have to create an extinction event for which there is no countermeasure.”

* Immunotherapy.  Toward this end, immunotherapy holds great promise.  So far, drugs such as ipilimumab and pembrolizumab have worked only in a few men – but these men haven’t just gotten a little bit better; they have shown spectacular improvement.  Tumors and metastases in these “exceptional responders” have melted away.

These drugs, called checkpoint inhibitors, work by “waking up” the killer T cells – white blood cells that, if unleashed, can viciously attack and kill cancer cells.  These cells typically don’t do much good against prostate cancer because, early on, cancer cells put them in a straitjacket.  Checkpoint inhibitors take the restraining bolts, or checkpoints, off of these T cells.   “When the T cells wake up, they can multiply and destroy faster than cancer cells,” Simons explains.  “If you have thousands of T cells against a single prostate cancer cell, the cancer doesn’t have time to mutate or hide; it’s just eaten up.”

Chemotherapy, when it works well, can do this, too, by a process of mass sterilization.  Stem cells within the cancer can’t replicate, and the cancer dies off.  “It’s like killing an entire squadron.  The cancer cells can no longer replicate.”  Chemotherapy for prostate cancer is much more selective than it used to be; side effects are greatly reduced, and normal cells are left alone.  “Amazingly, when this works, normal cells grow back in.  If you kill the cancer cells, it doesn’t leave a hole; your body will fill it in, just as if you’ve had surgery there.  It does leave a benign scar that you can see on a scan.  But when immunotherapy works, it causes the body to reject cancer just as it would try to reject a foreign organ.  We are just beginning to understand why some men are exceptional responders and others are not, and we are working to find ways to help more men become exceptional responders.”

  What can you do?  One very important thing: Donate to PCF. Any donation you make, of any size, goes right to research.  Two: Talk to your doctor about precision oncology, state-of-the-art treatments you read about here, to see whether any are right for you. One reason that breast cancer treatment has made so much progress is that women have been their own advocates, and they have helped to drive the cure.   Men with prostate cancer traditionally have not wanted to talk about it, have put off going to the doctor, and have not pushed for more answers.  This needs to change, and it is changing.  So, three:  Talk to other men about prostate cancer.  If they’ve never been screened and they’re in their forties, encourage them to go.  If they have cancer in their families, ask them to talk to their doctor about genetic testing.

* Roller coaster, or “bipolar” hormonal therapy.  Another approach that has shown promise at Johns Hopkins is to make cancer cells extra sensitive by giving high-dose testosterone after a course of ADT.  “It’s almost like they choke and die on a diet that’s too rich after they’ve been starved.  That is exploiting the understanding of stem cells.”

Studying this “stemness” means learning where cancer cells are vulnerable – it’s like the velociraptor testing the fences, except this time, we are the predator.   “Cancers that kill have this extraordinary property of renewal or evolution,” says Simons.  “A lot of our gene targets are these genes of evolution.  Normal prostate cells don’t evolve.  They’re the same as before.  But the children of prostate cancer stem cells keep mutating.  It’s evolution within your own body.”  Prostate cancer stem cells are like dandelion seeds, he continues.  “They’re there, even if they haven’t popped up yet.”  Finding a way to treat that one tiny, evolving bit of cancer, as soon as you see it – better yet, even earlier – may be the secret to extinction.

Where are we headed?

Curing oligometastasis:  Oligometastasis means you have just a few minuscule spots of cancer.  “If you have only three or four bits of cancer and we can see all of them, we can give SBRT and cure the cancer that way,” says Simons.  Note:  SBRT is stereotactic body radiation therapy, and its use here is different from its use as external-beam radiation therapy to kill the primary tumor in the prostate; instead of targeting the entire prostate, it is highly focused on areas just a few millimeters in diameter.   This new use for SBRT is now possible because radiation is better, and so is imaging; now doctors can actually see these tiny spots soon after they develop, and go after them.  Even a few years ago, this was not possible.  Men with oligometastasis may not even need to start hormonal therapy.

Liquid biopsy:  We are getting much better at detecting circulating tumor cells (CTCs) in the bloodstream – before these cells ever set foot on a new territory and start to establish themselves.  The next step after learning how to detect these cells reliably is learning how to treat them right there in the bloodstream.  “That’s how you treat HIV or tuberculosis or staph infection,” says Simons.  “You start treating based on a blood test, and you’re treating when there are much smaller amounts of disease present.”

Radiopharmaceuticals.  Scientists in Germany, testing a nanoparticle technique developed at Johns Hopkins by scientist Martin Pomper, can kill individual prostate cancer cells with a fluorescent die that targets PSMA, prostate membrane-specific antigen, a protein that’s only found on the surface of prostate and prostate cancer cells.  An imaging technique, called PSMA Pet scan, is available at a few centers here in the U.S.

The bottom line:  There is more hope now than ever.  Doctors used to tell men with advanced prostate cancer, “The medicines stop working, but we don’t know why.”  Now, we either do know why or we are learning.  We now know that there are genetic differences – in cancer cells, in hormone receptors, in proteins on those cancer cells, in molecules on the surfaces of T cells, just to name a few.  Every new bit of insight gives us a new target.

 

 

  What can you do?  One very important thing: Donate to PCF. Any donation you make, of any size, goes right to research.  Two: Talk to your doctor about precision oncology, state-of-the-art treatments you read about here, to see whether any are right for you. One reason that breast cancer treatment has made so much progress is that women have been their own advocates, and they have helped to drive the cure.   Men with prostate cancer traditionally have not wanted to talk about it, have put off going to the doctor, and have not pushed for more answers.  This needs to change, and it is changing.  So, three:  Talk to other men about prostate cancer.  If they’ve never been screened and they’re in their forties, encourage them to go.  If they have cancer in their families, ask them to talk to their doctor about genetic testing.

Terms to know from this article:

Gleason

Gleason Score (GS) - Gleason Grade: A system of grading prostate cancer cells based on how they look under a microscope. Gleason scores range from 2 to 10 and indicate how likely it is that a tumor will spread. A low Gleason score means the cancer cells are similar to normal prostate cells and are less likely to spread; a high Gleason score means the cancer cells are very different from normal and are more likely to spread.

Oncologist

A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation.

Metastasis

The spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a "metastatic tumor" or a "metastasis." The metastatic tumor contains cells that are like those in the original (primary) tumor. The plural form of metastasis is metastases (meh-TAS-ta-seez).

androgen

A type of hormone that promotes the development and maintenance of male sex characteristics.

Remission

A decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although cancer still may be in the body.

Abiraterone

Zitaga Abiraterone is an oral medication that blocks the synthesis of androgens (male hormones), such as testosterone, inside the tumor. Abiraterone is FDA approved for the treatment of patients with metastatic castrate resistant prostate cancer.

Testosterone

A hormone that promotes the development and maintenance of male sex characteristics.

Hormonal therapy

Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body's natural hormones. Sometimes surgery is needed to remove the gland that makes hormones. Also called hormone therapy, hormone treatment, or endocrine therapy.

Immunotherapy

Immunotherapy is a type of treatment that boosts or restores the immune system to fight cancer, infections and other diseases. There a several different agents used for immunotherapy; Provenge is one example.

Benign

Not cancerous. Benign tumors do not spread to tissues around them or to other parts of the body.

Biopsy

The removal of cells or tissues for examination under a microscope. When only a sample of tissue is removed, the procedure is called an incisional biopsy or core biopsy. When an entire lump or suspicious area is removed, the procedure is called an excisional biopsy. When a sample of tissue or fluid is removed with a needle, the procedure is called a needle biopsy or fine-needle aspiration.

Hormone

A chemical made by glands in the body. Hormones circulate in the bloodstream and control the actions of certain cells or organs. Some hormones can also be made in a laboratory.

Tumor

A mass of excess tissue that results from abnormal cell division. Tumors perform no useful body function. They may be benign (not cancerous) or malignant (cancerous).

PSA

prostate-specific antigen (PSA): A substance produced by the prostate that may be found in an increased amount in the blood of men who have prostate cancer, benign prostatic hyperplasia, or infection or inflammation of the prostate.

BRCA

Are a human gene and its protein product, respectively. The official symbol (BRCA1, italic for the gene, nonitalic for the protein) and the official name (breast cancer 1).

Gene

The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.

Janet Farrar Worthington is an award-winning science writer and has written and edited numerous health publications and contributed to several other medical books.

In addition to writing on medicine, Janet also writes about her family, her former life on a farm in Virginia, her desire to own more chickens, and whichever dog is eyeing the dinner dish.

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