Pills vs Shots for Androgen Deprivation Therapy (ADT)


To view this post on my blog site, see other essays, and sign up for future posts, please click here.

My own interest in prostate cancer began with what, in retrospect, seems quaint and naive. When I arrived at the University of Colorado in 1978, as the first board certified medical oncologist, there were very few clinical trials underway. Having trained (at DFCI) with teams of researchers, my philosophy had evolved to the thought that “every patient should be treated on a protocol, and there should be a protocol for every patient”. This idea (in academic centers, at least) is how we make progress in treating cancer. I continue to urge every patient to participate in clinical research whenever possible, recognizing that for reasons of geography, convenience, or eligibility, it may not be possible. Clinicaltrials.gov lists all of the ongoing clinical research trials for patients and physicians, a dramatic advance in keeping everyone informed. You can learn how to use this tool in one of my previous blogs, here.

With few clinical trials going on at our cancer center, I wrote a naive letter to a number of pharmaceutical companies asking if they had any drug development trials that I might participate in. A single company, Abbott, wrote back inviting me to Chicago to discuss “Abbott 43-818”. This drug was an analog of gonadotropin releasing hormone, GnRH, a peptide (10 amino acids in this case) that looks like this: Pyr-{His}{Trp}{Ser}{Tyr}{Gly}{Leu}{Arg}{Pro}{Gly}-NH2. The 43-818 analog came to be known as leuprolide, and I had the opportunity to participate in taking it all the way from the first dose in men to a final clinical trial resulting in its approval as Lupron™. I’ve been caring for prostate cancer patients and doing clinical trials in prostate cancer ever since – fate!

The way Lupron™ works is shown in the figure below. Normally a part of your brain called the hypothalamus (1) releases a “pulse” of GnRH several times/hour. The peptide travels to the pituitary gland (2) and lands on cells called gonadotropins, causing them to release hormones LH and FSH that travel to the gonads (4) where the ovaries release estrogen or the testes release testosterone. Leuprolide interrupts this process by “over stimulating” its receptor on the pituitary cells and they turn off their LH/FSH production. Because of the small and relatively simple peptide sequence 100’s of other analogs have been made, and the molecular interactions with the receptor have been extensively studied. Some are agonists (like leuprolide/Lupron™/Eligard™, or goserelin/Zoladex™ and others are antagonists (degarelix/Firmagon™).

The hypothalamic-pituitary-gonadal axis

After a long research path, an oral antagonist (relugolix/Orgovix™) has now been synthesized, tested, and approved for treating prostate cancer. It is not a peptide, has the advantage of not having to be injected, and may be safer in patients with a cardiac history. The HERO trial evaluated 934 prostate cancer patients, 2/3 of whom received relugolix and 1/3 received leuprolide. As expected (based on the history of antagonists research), relugolix resulted in more rapid reduction in testosterone, faster recovery upon discontinuation, and faster reduction in PSA.

The frequency of the common bothersome side effects, hot flashes and fatigue, was similar. More patients on relugolix (12.2%) had diarrhea than those on leuprolide (6.8%). However, the leuprolide treated patients had more serious cardiovascular events (myocardial infarction, central nervous system hemorrhages and cerebrovascular conditions, or death from any cause), especially if they had a cardiac history. The incidence was 6.2% in the leuprolide group vs. 2.9% in the relugolix group.

All things being equal, use of relugolix would seem to be a superior choice for ADT in prostate cancer patients. However, as usual, “all things” may not be equal. First, while the biology above may seem to favor the antagonist, there are no data on whether this affects survival or time to progression of prostate cancer. The biology of reducing testosterone as the mainstay of treatment has not changed – we are attacking the same target: testosterone stimulation of prostate cancer cells. Indeed, the more rapid recovery of testosterone upon discontinuation of therapy (for example in a patient who receives several months of relugolix in combination with radiotherapy) might result in better quality of life with rapid recovery, but have a higher rate of recurrence due to the shorter overall duration of ADT treatment. Some patients will prefer pills to shots. On the other hand, insurance coverage for injections might be much better than that for an oral medication. The internet reported cost for a month of relugolix is reported to be $2313. The cost for a one month leuprolide dose is around $1700. However, the cost of a myocardial infarction is not insignificant, and thus comparison of one form of treatment vs another is always more complex than it initially seems.

I am writing this because I suspect there will be “news” articles and other advertising efforts for “Orgovyx™” in coming weeks/months and I hope to refer my patients to this article (and all the other ones I write). If a newly diagnosed patient has impending spinal cord compression, or major organ involvement or a history of cardiac disease, I would recommend the antagonist (relugolix/Orgovyx™) over the agonists (like leuprolide/Lupron™/Eligard™ or goserelin/Zoladex™). If a patient is already on one of those agonists, is doing well and has no cardiac history, there is probably no reason to change therapy. For a patient who is about to start therapy, I will discuss the options, and am happy to prescribe either an agonist or antagonist – it may well depend on insurance issues for a given patient. As with the Covid vaccine, the scientific progress in developing a non-peptide, oral agent is a testament to “our” (medical science) phenomenal scientific advances. The cost of such research (dating back at least to 2013 for relugolix) and what represents fair costs to patients or to Medicare and fair reimbursement to the pharma companies remain concerning to me.

1 Comment

Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment, Uncategorized

Holiday greetings and philosophy


To view this on my website, search for other blogs, and sign up for future posts, please click here.

I want to wish all of you a very Merry Christmas, happy holiday (whichever ones you celebrate or just celebrated) and a safe and vaccinated New Year. And most of all, THANK YOU to the many folks who contributed to my annual Movember Moustache. We again blew the top off my goal, and it makes me abundantly happy to join you in supporting the research into prostate cancer survival and cure.

Second, I urge you to hang in there, wear your masks, and limit the Christmas interactions. We only have a couple of months to go before we are vaccinated if you are in my age bracket, so stay the course!

Finally, I will share the thoughts of my Department of Medicine Chairman, David Schwartz who has put as fine a summary on where we have been and where we need to go as I have seen. I hope you will find it encouraging:

“A number of months ago, I wrote that ‘Science will lead our way out of this crisis.  Basic modeling and infectious disease epidemiology has helped us understand what’s coming, the science of social distancing, clinical trials have identified remdesivir as a promising agent, novel serologic assays will identify the extent of disease in our communities, and vaccine development will provide the cure.  All of this takes investment, and now is not the time to back away from our scientists or our scientific infrastructure.  In fact, now’s the time to double down.  We still have to get through this crisis but rest assured there will be human health challenges in the future, and we need to be ready.’  

Now with the demonstrated importance of social distancing, the improved care of patients with Covid, and the FDA emergency use approvals of the Pfizer and Moderna vaccines, it’s time that we recognize and celebrate the truly remarkable advances in our fight against Covid that have been made since the initial transmission of SARS-CoV-2 in the Huanan Seafood Wholesale Market only one year ago.

·         Social distancing:  The past few weeks have demonstrated the profound effect that social distancing has had on the transmission of the virus.  The story of the coronavirus in America is a compartmentalized one, with different places experiencing different spikes for different reasons at different times.  Fortunately, over the past week in Colorado, there’s been an average of about 3,100 cases per day, a decrease of 28% from the average 2 weeks earlier.  This decrease in cases per day in Colorado is reflected in the census data in our hospitals, and the state-wide hospitalization data with both peaking and slowly going down since the beginning of December.  In contrast, over the past week in the entire U.S., there’s been an average of about 220,000 new cases per day, an increase of 19% from the average 2 weeks earlier.  Continue to wear a mask, practice social distancing, and don’t travel over the holidays.

·         Clinical trials:  Over the past year, well-conducted clinical trials (by many of our investigators) have identified what works and what doesn’t.  Our improved ability to take care of patients with SARS-CoV-2 infection is reflected in the decreased percent of patients requiring ICU care (55% last spring – 40% now) and a decrease in the number of patients in the ICU requiring intubation (90% last spring – 67% now).  Moreover, the survival and re-admission rates continue to improve among our Covid patients.

·         Vaccines:  One year ago, very few people would have predicted that we would be embarking on a vaccination program with two extremely effective vaccines with minimal side effects.  This was not a miracle.  The development of these vaccines were enabled by many scientific accomplishments (bat virology, DNA sequencing, computational biology, and basic science of RNA, proteins and lymphocyte biology to name a few) that have been supported by the federal government, industry, academia, and public-private partnerships.  Investments in science are essential to our future.

I think there are other take home-messages that will continue to strengthen the scientific programs on our campus:

·         Team science and scientific partnerships are critical to combining clinical insights with cutting–edge research.  Collaborations and social networking will improve the efficiency of research.  We need to foster these interactions.

·         Public-private partnerships (like the one between the NIH and Moderna) can lead to powerful advances and need to be nurtured.

·         Our nation has to place a higher value on science.  Part of this involves public education and we’ve got some real opportunities with our patients.  However, we should also do everything possible to help Congress recognize the sad lessons learned from the ways science has been pushed aside during the pandemic, and strongly advocate to substantially increase the federal research budget.”

To all of you who subscribe to this blog, I thank you for your interest, ideas for topics, and your support for the physicians, nurses, staffs and researchers who have made it possible for all of us to live longer and healthier lives than any generation in history. It has been an incredible journey for most of us and in spite of the 2020 “downer” we have much to be thankful for. Keep exercising and my best wishes for the New Year!

3 Comments

Filed under Uncategorized

Epigenetics


To view this post on my blog site, sign up to receive future posts, or search for past topics, please click here.

One of our faithful readers suggested this topic. My first introduction to the concept of epigenetics may have been in a lecture that the late Don Coffey gave at a course I helped organize at the Given Institute in Aspen which still goes on today. Don was a pied piper to hundreds of students at all levels at Johns Hopkins, and on his first visit to the course told them about arriving late at the Denver airport, driving his rental car too fast over Vail pass, then exiting and hiding under a bridge while a State Patrol car zoomed over him, and getting back on the road to make it to Aspen just in time. Not a bad way to endear yourself to some younger physicians in training!

His signature illustrative story was that of the fertilized hen’s egg. There it sits, with all the information needed to make a full chicken encoded in the DNA, but nothing happens until it is put in an incubator and the temperature rises. Only then does the machinery kick in to go from a single cell to billions of cells with everything from feathers to an intestinal tract. “How does that happen?”, he would ask, and then proceed to talk about how the DNA is wrapped around histones as shown in the following illustration:

Dr. Coffey would then show pictures of DNA in prostate cancer cells, some of which was compactly wound around the histone proteins (and therefore inactive) and some of which was “open for business” with long loops of DNA strands sticking out from a chromosome. I love the simplicity of this illustration, because it demonstrates how not only temperature can influence the long string of base pairs that otherwise are the deceptively simple ATCGTCCATA… code, but also begins to explain how environmental factors, drugs, aging, and diet can change gene expression. My hiking friend, who is somewhat of a eugenics devotee, thinks mankind will evolve to [his view of] perfection by using CRISPR to modify just the DNA sequence and change everything from physiognomy to behavior. I, of course, disagree based on epigenetics. A woman in her first trimester who eats too much broccoli one evening might well affect her child’s math score by 1/10 of a point…

But back to prostate cancer! As shown in the above figure, one of the common ways genes and their expression is modified is through methylation. The chemistry is shown in this figure and a complete article on DNA methylation from Wikipedia is here.

This image shows a DNA molecule that is methylated on both strands on the center cytosine. DNA methylation plays an important role for epigenetic gene regulation in development and cancer. [Details: The picture shows the crystal structure of a short DNA helix with sequence “accgcCGgcgcc”, which is methylated on both strands at the center cytosine. 

These methylation changes are frequently found in what are known as CpG islands, or areas of the genome that are rich in Cytosine Guanine base pairs, and particularly in the so called “promoter regions” upstream from the gene itself that control whether the gene is “active” or not. In prostate cancer, methylation of an enzyme called GSTP1 was one of the first methylation markers that became useful in detecting prostate cancer. If a man with a highly suspicious rise in PSA was biopsied and there was no cancer found, if the biopsy of the “normal” tissue next to true cancer was analyzed and methylation of GSTP1 was found, it was highly predictive that real cancer was present but just missed. As time went on, many other genes with hypermethylation changes were found, and panels of such genes could be used to detect prostate cancer cells in the urine, potentially replacing invasive biopsies. More recently, utilizing advanced techniques to search for methylation patterns in the whole genome, it has been possible to find markers (probes) for genes (see this article) which are differentially methylated in prostate cancer and have dramatic prognostic significance. Here is one such example showing that depending on which form (allele) of a gene called ATP2A3 (that can be methylated or not) you inherit, it can affect your survival.

The homozygous alternative genotype of a haplotype on chromosome 17, associated with methylation of ATP2A3, gives a survival advantage. HR and P values are from the CoxPH model.

Although much of the article from which I copied that figure is way (WAY) over my head, the point of understanding epigenetics is that prostate cancer is much more complicated than just a mutation or two in some cancer causing genes. The expression of a myriad of other genes that can be controlled by methylation or other epigenetic processes can play a major role in what happens to us. As it turns out, this week’s NEJM has an article specifically related to the epigenetics of prostate cancer as it evolves from localized to metastatic. Here is the key illustrative figure and accompanying explanation.

Figure 2. Epigenetic Regression with Clinical Progression of Prostate Cancer. Pomerantz and colleagues4 describe epigenomic patterns that occur in the transitions from the normal human prostate gland to organ-confined prostate cancer to metastatic castration-resistant prostate cancer, with their findings regarding metastasis relying largely on patient-derived tumor xenograft models. Sites of androgen-receptor binding in the genome have been associated with this transition from normal prostate gland to metastatic disease. Such binding sites are “premarked” by the transcription factors HOXB13 and FOXA1. Also, the researchers found that sites that are specific to metastatic castration-resistant prostate cancer correspond with sites in the open chromatin state in the normal prostate gland and in organ-confined prostate cancer, which indicates a lower barrier to reprogramming to a metastatic state. The epigenome (H3K27 acetylation) pattern in prostate cancer metastasis was similar to that in fetal (but not adult) prostate cells. A limitation of the study is that it does not include an analysis of circulating tumor cells or metastatic castration-sensitive prostate cancers.

As this story unfolds, “precision medicine” will become a way to individualize prostate cancer treatment. However… the heterogeneity of prostate cancer metastases will remain a major challenge in the practical application of such knowledge. Meanwhile, if you haven’t already supported prostate cancer research through my Movember effort, feel free to wander over to my website and make a contribution – and THANKS to all of you who helped me reach my goal!

Leave a comment

Filed under Uncategorized

Yay – Voting is over and it’s Movember y’all


Every year, in honor of the guys I care for and the progress Movember has made in supporting research for prostate cancer, I join in the effort to raise funds from my faithful readers. This year is no exception. 2020 has been such a downer, we all need to do something positive to make ourselves feel better. So, if you can spare some change, I humbly ask you to support my annual scraggly moustache, and I can assure you the funds are well spent. For example, new tests are coming out of labs Movember supports. They constantly update the priorities as you can see in this article, and support ongoing clinical trials like this one. And for men isolated in our COVID times, there is the kind of support you need when facing tough questions at “Men Like Me“. In short, I hope you will help me with a donation to my Movember effort by clicking here:

Mike’s Movember Website

  • Then click the DONATE BAR under my picture: (not the one at top right)

For donors of >$50, I have ordered some Movember Moustache masks and will send you one. And for all participants, let’s plan on a zoom celebration in December – maybe I can answer questions sent in on chat or similar. If you are more savvy than me, scan the following image on your smart phone to be taken to my Movember webpage. And THANKS for your consideration and help!!!

1 Comment

Filed under Uncategorized

Nex Gen Diagnostics and Treatment


To view this on my website, sign up for future posts, and search for previous topics, please click here.

When I was a fellow in Dr. David Livingston’s lab 40+ years ago, DNA sequencing had just become “widely” available, developed by Maxam and Gilbert. There was a brilliant MIT student, 16 years old as I recall, who visited the lab that summer and brought his TI calculator to the lab, assigning a number (1,2,3,4) to each of the bases and would go into David’s office with a string of numbers to look at. The evolution of that technology to what goes on today when you send in a saliva sample to 23 and Me is shown in the following video:

This video explains next generation DNA sequencing

With what seems (to an old guy like me) shocking speed, the human genome was unraveled and with it, all (most?) of the genes that control cellular processes including cancer. As I have recommended before in this blog, for a fabulous review of the story, I recommend you read “The Emperor of All Maladies” by Siddhartha Mukherjee.

Due to the power of DNA sequencing it is now possible to obtain DNA that originates in tumors and do sequencing of cancer causing genes directly from the blood stream or from the urine or other body fluids. This is a so-called “liquid biopsy“.

The entry of this technology into caring for cancer patients has also been incredibly rapid. At the present time, for prostate cancer, the NCCN patient guidelines are a great place to start learning about pca in general if you are new to the topic, but the physician NCCN guidelines are much more specific regarding what you need to know about your genetics. Here are the recommendations for “germline” testing, i.e. what you have inherited that may have pre-disposed you to develop prostate cancer and what might affect other members of your family including children or siblings:

The guidelines are also very informative about this testing being done with the help of professional genetic counsellors:

Genetic testing in the absence of family history or clinical features (eg, high- or very-high-risk prostate cancer) may be of low yield.
• The prevalence of inherited (germline) DNA repair gene mutations in men with metastatic prostate cancer, unselected for family history (n = 692), was found to be 11.8% (BRCA2 5.3%, ATM 1.6%, CHEK2 1.9%, BRCA1 0.9%, RAD51D 0.4%, and PALB2 0.4%). The prevalence was 6% in the localized high-risk population in the TCGA cohort (Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011-1025; Pritchard CC,Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443- 453).

• Genetic counseling resources and support is critical and pre-test counseling is preferred when feasible, especially if family history is positive.

• Post-test genetic counseling is recommended if a germline mutation (pathogenic variant) is identified. Cascade testing for relatives is critical to inform the risk for familial cancers in male and female relatives.

https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

However, as noted above, we can also sequence the tumor itself or look for mutations in tumor DNA that is circulating. The most important thing that may show up in these analyses is a mutation that can be specifically targeted with one of the newer drugs. Examples include the finding of a DNA repair gene mutation such as BRCA1 or BRCA2 in which case the use of a category of drugs called PARP inhibitors or platinum based chemotherapy might be an important consideration for patients who have failed hormone therapy. Thus, we now utilize DNA sequencing both in patients who have family histories for certain cancers, patients with metastatic disease, high risk disease, and again when there is progression of the cancer after hormone treatment stops working. Beyond these impacts of DNA sequencing are the many gene-based tests that have evolved that can help determine risk for finding prostate cancer on a biopsy, or predicting whether someone is at high or low risk for metastatic disease after a positive biopsy and Gleason score is known.

I tried to help understand the complexities of integrating all of these new tests and therapies in this blog. Although it may be difficult to keep up with this rapidly evolving landscape for both patients and physicians, there is no doubt that we have entered the “next gen” era of prostate cancer management. Finding an expert who focuses on pca and discussing some of the issues raised in this blog is key to taking advantage of what is being learned. Hopefully this blog will help you become a better informed member of your team in terms of the underlying technology. For a more erudite discussion of cancer precision medicine, you might read this newly posted discussion.

5 Comments

Filed under Uncategorized

Why can’t we cure this???


To view this post on my blog site, sign up for future posts, or search for other topics, please click here.

A frustration for patients and physicians alike is the incurability of metastatic prostate cancer in spite of the great response that many/most patients have to initial hormonal treatment. As most readers of this blog know, almost all prostate cancer cells depend on stimulation from testosterone to grow and to get outside the prostate, moving to lymph nodes or bones (the most common place for metastases in pca). Testosterone is normally made by the testes and adrenal gland, circulates in the blood stream, and enters the cancer cells where it binds to the AR (androgen receptor). The AR then translocates to the nucleus where it binds to specific locations “upstream” from various genes (including PSA, and interestingly TMPRSS2 which has implications for COVID-19) leading to the gene being “activated”. Many of the activated genes lead to cell division and invasion that characterize/lead to metastases we detect with bone, CT, or PET scans.

Normally, the way we detect that cancer cells are “turned off” or dying is by the PSA falling. PSA in general is far more sensitive than scans, but it really tells us about the “big picture”, not what is going on with individual collections of metastatic cancer cells. Measuring PSA every 3 months is a very common way to monitor the response to drugs that stop testosterone synthesis (abiraterone – Zytiga) or block testosterone from binding to the AR (bicalutamide-Casodex, enzalutamide-Xtandi, apalutamide-Erleda, darolutamide-Nubeqa)

Although much more expensive, monitoring response by repeating scans can begin to answer the question posed for the title of this blog. Why doesn’t hormone therapy lead to cures? The reason lies in a single word, heterogeneity. As I reviewed previously, when we look at different sites of cancer metastases, the tumor deposits in one area may have a very different genetic mutation profile than those in a different area. I was very struck by how well this is illustrated in a recent article using quantitative PET scans. In patients treated with enzalutamide, the different sensitivity is graphic as shown in this figure from the article:

Compare PET1 taken at the start of treatment with enzalutamide to PET3 when disease was progressing indicated by a rising PSA. Green spots indicate partial or complete response to the antiandrogen while red ones are new or progressive locations. This is a graphic example of the result of tumors having genetic changes that make them more or less sensitive to the drug. Finding a combination of chemotherapy or hormone therapy that can attack all of the genetically different deposits is impossible at this time. However, the immune system may be able to keep up with all the changes in some patients, and this provides hope for the expanding trials of immunotherapy in prostate cancer you can find here. Glass half full or half empty? You choose!

6 Comments

Filed under Uncategorized

Prostate Theranostics


To view this on my blog site, sign up to be notified of other blogs, and look for other posts related to prostate cancer, please click here.

Sometimes a great new word evokes curiosity, so I have used it to title this post and see if a few of you thought it would be worth looking at rather than sending to your “junk” email. You can’t find it in the dictionary, interestingly enough, but it’s related in derivation to Theranos, the bizarre company started by Elizabeth Holmes and if you haven’t read “Bad Blood” or seen the video you can find that story here:

For us prostate cancer followers, however, theranostics represent a “new” field in which the same/similar drugs can potentially be used for both diagnosis and therapy. There is a nice review of an ASCO educational presentation on the topic here. The main idea is that a radioisotope can be specifically directed to a target for either diagnosis or therapy. One of the oldest examples of this is radioiodine which is taken up by the thyroid gland. If you have thyroid cancer, the metastases will also take up the radioactive iodine and with nuclear medicine detectors you can see them, or if you inject even more, it will be “hot” enough to kill them.

223Ra is an isotope that seeks bone, just like calcium, and where there is more bone turnover/remodeling, more of it accumulates. As a drug, it was given the name Xofigo, and was approved for treating prostate cancer in men with bone dominant disease in 2013. It emits alpha particles, which are known as “high Linear Energy Transfer” radiation because they go only a very short distance before interacting with cancer cells and killing them. This is important since you would not want the radiation to kill the normal bone marrow cells that live in the same neighborhood. In the study leading to approval of 223Ra, men with symptomatic bone metastases and no visceral (e.g. liver or lung) metastases who received the isotope as a monthly injection for 6 months lived 14.9 months as compared to 11.3 months for placebo (P<0.001) and had fewer skeletal events and less bone pain. I always loved alpha emitters because I had the fun of making a cloud chamber for a science fair when I was in 6th grade. You might want to help a grandchild do that!

177Lutetium (177Lu) is an isotope that allows both diagnosis and therapy because it emits gamma radiation for detection, and high energy beta radiation that can kill cancer cells. When bound to PSMA (see these posts)

177Lu becomes a theranostic that shows considerable promise for treating prostate cancer. There are a number of completed trials of 177Lu-PSMA that have been summarized in this table:

For more details on 177Lu-PSMA treatment, this is an excellent recent review from the European Society of Radiology:

https://epos.myesr.org/poster/esr/ecr2020/C-00307

There are a number of ongoing trials of 177Lu-PSMA that you can find here.

Keep wearing your masks to protect your fellow prostate cancer groupies, be patriotic, and if you want to pay homage to one of the great scientists whose research led to these advances, look no farther than Radioactive, the recent Amazon Prime movie about Marie Curie. As one of the commentators on the trailer posted, “In a world full of Kardashian’s… be Madam Curie.”

9 Comments

Filed under Uncategorized

CAR-T and related immunotherapies


To view this on my blog site, see other blogs, and sign up for notification of future posts, please click here.

One of your co-subscribers to this blog contacted me and asked if I would write a blog about CAR-T cells, and I have decided to include the closely related bi-specific antibody therapies. I am very intimidated by even attempting this, because the complexities of this field are daunting, so please do NOT show this post to your PhD immunologist cousin.

As most readers probably know, the immune system consists broadly of the “humoral” and “cellular” arms. When you get corona virus, (or any other virus) both arms are activated. Broadly speaking, your B-cells (lymphocytes that live in the lymph nodes and also circulate in your blood stream) make antibodies that attach to targets (“antigens” – in the case of corona virus, the spike protein you are tired of looking at on TV is the target antigen we hope a vaccine can be made from) and can inhibit the virus or can clear the antigen from your circulation. Antibodies consist of proteins (chains) that combine with each other and this is where things start getting VERY complex, but a single B-cell can make only one type of antibody (called a monoclonal antibody). Whether you know it or not, if you have an interest in prostate cancer, monoclonal antibody technology is “why you are here” – PSA detection was made possible by isolating a monoclonal antibody that would bind to Prostate Specific Antigen. But with modern recombinant DNA techniques, the chains that make up these antibodies can be combined in highly variable ways never found in nature. The history and complexity of the antibody story is illustrated here from this article. Screen Shot 2020-06-13 at 10.31.25 AM

The Y-shaped figure above is “an antibody” and the colored chains are the proteins in the antibody that can be extremely variable and give the antibody its ability to bind to any target. Note that the two arms of the antibody could be designed so that one arm would bind to one target and the other arm could bind to a different target. Voila! You could design one arm to bind to PSMA and another to a killer T-cell that would link a killer cell to your cancer cell.

Screen Shot 2020-06-13 at 10.42.33 AM

 This is the general idea behind an innovative cancer approach you may hear about called BiTE. In this figure, the working part of the tips of two “Y” antibodies have been linked and when injected into a patient, in theory the “killer” T-cell is forced to bind to the tumor cell via its “TAA” or tumor antigen. If you are a dedicated reader of this blog, you already are thinking about a great target antigen I previously introduced you to, PSMA

Now on to my VERY oversimplified description of CAR-T cells. The terminology refers to Chimeric Antigen Receptor – T cells. The science of these is related to the above description of antibodies in the following way: On the surface of the T-cells in your lymphocyte library is a completely different group of proteins that allow the T-cells to bind to and recognize antigens, much like the antibody system we discussed above. These proteins combine in chains on the surface of the cells to form “T-cell receptors”. Unlike the antibody system, their interactions with antigens are further modified by requiring recognition of “self”. Non “self” is why people who receive a kidney or heart transplant must receive drugs to suppress the immune system that will reject the transplant. Unfortunately cancer cells are mostly recognized as “self” so we don’t reject them. BUT… again using recombinant DNA technology, the T-cell receptors (TCR) can be re-designed so they DO recognize a tumor target, even though it is “self”. You can start with lazy, somewhat unresponsive T-cells that might be in the blood or even infiltrating a tumor, take them out, modify the receptor (dramatically as shown in the following figure), and force them to recognize a cancer, then re-infuse them into the patient like any blood transfusion.

Screen Shot 2020-06-13 at 11.02.34 AM

In the figure (taken from this article), the “antibody like” part of the receptor that controls “self” is CD3 and the “antibody like” part of the TCR receptor that binds to a tumor antigen or virus infected cell are the green proteins marked alpha and beta. The recombinant magic that is WAY beyond this blog is everything on the right. If you have the time and interest in really delving into CAR-T therapy for cancer, you really do have to read this article. But, for those who wonder “so why aren’t we doing this?”, the Cliff’s Notes answer is that (1) it is VERY expensive – each patient has to have his/her T-cells taken out and modified, expanded, then re-infused; (2) it has only worked well for blood cancers like leukemias so far; and (3) even though PSMA or some similar tumor target might be thought to be “tumor specific”, it turns out these targets are often expressed in low levels in places like your brain or lung. When the CAR-T cells begin attacking your normal tissues, you are in a world of hurt. If you have followed the COVID-19 story, you may have heard about the “cytokine storm” that is killing people by destroying their lungs. As you might imagine, combining these approaches with the other “hot” area of immunotherapy, the PD-1 inhibitors I have previously written about could make CAR-T treatment more effective but the toxicities even worse.

I hope this has been helpful and that your immunologist cousin or highly informed oncologist will forgive the effort to simplify a very promising but challenging field. I’m also grateful to the myriad of incredible researchers who have put this all together for us “cancer fighters” and their dedication is equally as worthy of honor as other warriors on front lines.

 

 

 

 

3 Comments

Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

COVID-19 and “the news”


To view this on my blogsite, read other blogs, and sign up for future postings, please click here.

This won’t be a long blog, but since I anticipate lots of news this week regarding an article that was published a few days ago, I thought I would provide a “heads up” to my prostate cancer “groupies”. What makes the news and becomes “viral” is interesting and I haven’t had the opportunity to watch the sequence up close personally before. My wife is a pediatric infectious disease expert with specific interest in Kawasaki Disease. As you most likely have seen in the news over the past few days, SARS CoV2 now seems to trigger a KD type of illness in children. This became apparent a little over a week ago with calls flying back and forth from around the world among her friends, notably because Michael Levin, from London had seen some cases and sounded the alarm among the international colleagues. So, from “insider info” to public alarm seems to take about a week.

As you know from faithfully reading this blog, I predicted that men on androgen deprivation therapy might be protected from SARS CoV2 about 6 weeks ago and that physicians/scientists with access to large databases would be able to show this. And, true to the prediction, this past week an article appeared showing just that. I have summarized the data for you on this slide:

Screen Shot 2020-05-10 at 8.33.47 AM

It will be interesting to see this get picked up and “sensationalized” by the media over the coming days. And it is already underway. I am aware of a conference call with the CDC and another being hosted by the Prostate Cancer Foundation this coming week. So consider yourselves forewarned! CNN, FOX, ABC, etc. etc. will be all over it…

Now, as I also predicted, I would bet that there will be prospective studies looking at ADT as a form of therapy for COVID19 starting soon (if not already underway). My favorite design would be with the approved agent, remdesivir in a randomized prosepective trial. Male patients sick enough to be admitted to a hospital would all receive remdesivir, and 1/2 would receive ADT in the form of an anti-androgen (e.g. enzalutamide, apalutamide or darolutamide) or a single injection of a month of a GnRH analog like degarelix (Firmagon), or the androgen synthesis blocker abiraterone/prednisone (Zytiga). I would hope that this kind of approach could help men (and maybe even women) fight the virus by blocking TMPRSS2 as I previously showed you in the graphic on the original blog. Now YOU are the insiders!

PS, I think that another approach could be starting everyone in a nursing home “under attack” could be starting all the occupants on finasteride. Blocks DHT production from T and is very well tolerated in the  pcpt trial. Lower DHT -> lower TMPRSS2 -> lower viral replication.

12 Comments

Filed under General Prostate Cancer Issues, Prostate cancer therapy, Uncategorized

PSMA PET-CT scans for Prostate Cancer


To view this on my blog site, search for other blogs of interest or sign up to be notified of future blogs, please click here.

PSMA stands for Prostate Specific Membrane Antigen, which is a protein (enzyme) that is expressed on the surface of prostate cancer cells (and on a few other cell types). As with many cell surface proteins, you can find ligands that will bind to the protein, and then label these with radioactive isotopes that allow imaging. PET stands for Positron Emission Tomography, and of course, CT stands for Computerized Tomography. When you put these technologies together, you obtain a powerful way to look for prostate cancer that has spread outside the prostate gland. The physics of this (how a positron interacts with an electron, releasing gamma photons at 180 degrees) is very cool, but probably of interest only to the most nerdy. (I made a cloud chamber for my 7th grade science project and my hiking buddy is a nuclear medicine doc who wrote a definitive text on the math/science of his craft…so go figure).

Prior to developing PET agents for prostate cancer, we had standard CT scans and bone scans and we used these to determine whether someone with, for example, a very high PSA or high Gleason score had cancer deposits that had escaped (metastasized) from the prostate. If so, it was felt that putting them through surgery or radiation treatments in an attempt to cure was fruitless and exposed the patient to the unnecessary toxicity risks (impotence, incontinence, rectal damage, etc.) Especially if they had symptoms (e.g. bone pain), hormone treatment reducing testosterone was the best approach. If you had a rising PSA several years after local treatment, the question was always, “Where is the cancer?” but the sensitivity of routine bone and CT scans was quite limited not showing anything until the PSA reached 10 or so at which time ~1/2 of scans would be positive. Screen Shot 2020-04-26 at 7.26.14 AMThis figure illustrates the difference in sensitivity. A normal sized lymph node on CT scan (left) is revealed to  contain prostate cancer with the PET isotope technique (right). At present, the only approved PET scan in the U.S. is fluciclovine, the “Axumin” scan, which the FDA approved for detecting cancer in patients with rising PSA, but not in newly diagnosed patients. In several studies PSMA-PET CT scans are even more sensitive (about 3x) than Axumin. At the risk of calling up an overused phrase, “this changes everything”.

First, it is clear that many high risk patients we would previously have treated with surgery or radiation to the prostate hoping to cure them might now be found to have prostate cancer deposits outside of the treatment target (prostate or prostate + pelvic lymph nodes). A superb study in this month’s Lancet found that PSMA PET-CT scans provided higher sensitivity (85% vs 38%) and specificity (98% vs 91%) than routine bone and CT scans in high risk patients (PSA >20, Gleason 4+3 or worse). Does this mean we shouldn’t treat the prostate in high risk patients with positive scans? In the study, conventional imaging changed the management in 15% of men, while PSMA PET-CT imaging changed the plans in 28% (p=0.008). Should all high risk patients have a PSMA PET-CT before deciding on treatment? Should the FDA approve this scan quickly? (It is currently available only in research centers and not covered by insurance…read my blog on how to search for such studies or click here).

Second, what about treating a small number of prostate metastases (oligometastatic prostate cancer) in a patient who was treated years ago and now has a rising PSA? Ongoing investigations suggest this might delay the need for hormone therapy in such patients or potentially even cure some of them. But the PSMA PET-CT isn’t perfect. How high do you let the PSA go up before ordering such a scan? – the farther it rises, the more likely the scan will show something, but that gives the cancer more time to spread. A negative scan is no guarantee there aren’t many more foci of a few prostate cancer cells that will eventually show up elsewhere in the body. Is this some version of Whack-a-mole? And how do we define “cure” anyway?? (My personal definition is that you die from something else, regardless of your PSA or scan results).

Finally, since even at research centers the PSMA PET-CT scan may cost you $3,000 or so, is it worth it? It is “free” in the European health care systems, but we all know nothing is free – even if Medicare pays for something it costs society and ultimately must be accounted for in terms of value. Medicare covered PSMA PET-CT’s vs fixing pot holes and bridges? How about finding a treatment for SARS Co-V2 instead? No easy answers, but if you are like me, homebound as a “high risk” senior citizen, plenty to think about. Wash your hands, wear your mask, and enjoy your grandkids on Zoom!

11 Comments

Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Targeted treatment