Why can’t we cure this???

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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

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6 responses to “Why can’t we cure this???

  1. neikter

    But is there not a discussion regarding oligometastatic state discovered on PSMA?

  2. Andrew Kaufman

    Thank you for the wonderful, informating post.

    Andrew B. Kaufman, M.D. 970.477.2500 (Vail) 913.677.4392 (Kansas City) 816.210.4392 (cell) 913.677.4392 (fax) 251 94 477 33 23 (Ethiopia)

  3. Dennis Doyle

    Prostate cancer at its origin ( in the gland) is often heterogeneous so it is no surprise heterogeneity continues as it enters the lymphatic or vascular system with further mutations occurring once the blood supply has been established to the metastatic tumors. To my knowledge, the development of medicines known as checkpoint inhibitors are the first immunological breakthrough for cancer. The “ Checkpoints “ being “ inhibited” are certain cell proteins made by immune system cells , such as T cells. Once those “ blocking cells “ are inhibited from blocking the T cells , the T cells can kill the cancer cells. What Dr. Glode can tell us is how many “ blockades “ might exist that disrupt T Cell activation. Said otherwise, how many “ inhibiting medicines “ will have to be developed to unblock the blockades. Or is it that simple. Does the entire immune system need to be massively recalibrated to be taught to see and kill all cancer cells ? And how might that happen.?

  4. Wow – great comment and insights Dennis! My very first lab project as a medical student in 1970 was with a brilliant guy, Stu Kornfeld, who is in the National Academy of Sciences and we were trying to purify a protein(s) from the thymus gland we called “chalones”. Fast forward 50 years and we now know the dozens of immune related proteins as interleukins, interferons and cytokines. My view (amateurish to be sure) is that your thinking about massive recalibration is probably exactly what is needed. Turning on an immune response in the whole body is a disaster if it gets out of control. Turning on a local immune response might be easier, but would then run into the same issues of heterogeneity. A good thing about the immune system as opposed to a chemical drug (“chemo”) is that it might be able to adapt to the cancer’s mutational changes rather than just hit a single target like a specifically mutated gene or pathway. (Think of parp inhibitors for BrCA mutated patients) Mother nature has had a VERY long time to calibrate the immune system to turn on and off to fight foreign invaders. Cancer that develops within us is not really that “foreign” and that’s the real problem.

    • A couple of further thoughts: 1) the check point inhibitors and cytokines all have significant side effects – as bad as “chemo” in many cases. An example is this week’s nejm article on use of avelumab (a PDL-1 inhibitor) for maintenance in urothelial cancer. Things like fatigue, rash, fevers, diarrhea, hypothyroidism, arthralgia, etc were all far more common in the treated than the control group, even though the treated group did indeed live longer. 2) The proteins we discussed are only half the story. Cellular immune regulation occurs via cells like T-regulatory cells which can also exert powerful suppression of immune responses.

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