Monday, September 26, 2022

What Causes Castrate Resistant Prostate Cancer

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Psma Targeting Agents In Trt

Understanding non metastatic castration resistant prostate cancer with Dr. Hamilton

The extracellular domain makes up to 95% of PSMA and provides an accessible target for small molecules, antibodies, and their fragments . A number of PSMA-targeting small molecules and antibodies have been developed for molecular imaging by single-photon emission computed tomography and PET and/or TRT . Small molecules offer potential advantages over antibodies, such as small size, easy synthesis and modification, high specificity and affinity, good permeability with rapid accumulation in tumor, and rapid clearance from most normal tissues .

Several antibodies and their fragments are also being evaluated for TRT in preclinical and clinical studies . The antibodies J591, 107-1A4, PSMA-TTC, and their conjugates recognize extracellular epitopes of PSMA and are the most investigated for TAT . J591, 107-1A4, and PSMA-TTC were described and characterized in 1997 by Liu et al. , in 1998 by Brown et al. , and in 2020 by Hammer et al. , respectively. The half-life of the radionuclide must be matched with the antibody residence time in the tumor to deliver the maximum irradiation dose . Antibodies have a plasma half-life of about 27 days, and several days are needed to reach maximum tumor uptake . Radionuclides with too short or too long half-lives may lead to suboptimal efficacy or toxicity.

Intermittent Versus Continuous Hormone Therapy

Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent treatment. The hope is that giving men a break from androgen suppression will also give them a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time for example, 6 months on followed by 6 months off.

At this time, it isnt clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

The Role Of Ar Signaling In Crpc

The expression of PSA is mediated by androgen response elements. This suggests that the increasing PSA during ADT reflects activation of AR transcriptional activity. Consistent with this hypothesis, various recent findings have supported the notion that one of the most important mechanisms in CRPC development is the continuous activation of AR in prostate cancer cells. Several cellular and molecular alterations are related to this post-castration activation of the AR, including incomplete blockade of AR-ligand signaling, AR amplifications, AR mutations, aberrant AR co-regulator activities and AR splice-variant expression.

Enzalutamide is a novel AR antagonist that overcomes resistance to conventional anti-androgens by inhibiting nuclear localization and chromatin binding of AR. According to a recent phase I/II study in patients with mCRPC, the use of enzalutamide is safe, elicits PSA and radiographic response, and results in a median time to progression of 47 weeks. The superiority of enzalutamide over placebo was confirmed in a phase III clinical trial that showed increased overall survival and improvement in all secondary end points in patients with mCRPC after chemotherapy. Despite these encouraging results, after a period of remission that is characterized by significant variation in therapeutic response, these tumors eventually progress.

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Survival Of Men With Metastatic Castration

There has been regular discussion here and elsewhere about the degree to which new forms of therapy have impacted patient survival since the original approval of docetaxel for treatment of metastatic, castration-resistant prostate cancer . The one thing that has always been clear is that one couldnt just add up the median survival benefits of all the new drugs and assume that the total would be the degree of absolute benefit.

We had not noticed this at the time, but as of February 2018 we have had some much more concrete information about this topic from one of the very best cancer centers in the world: the Dana-Farber Cancer Institute in Boston.

At the Genitourinary Cancers Symposium in San Francisco, earlier this year, Francini et al. reported data from a total of 583 patients, all diagnosed with and treated for mCRPC at DFCI and whose data were compiled in the DFCI Clinical Research Information System.

Francini et al. subdivided these patients into two cohorts, as follows:

Here are the core study findings:

  • Average follow-up was
  • 10.6 years for patients in Cohort A
  • 4.6 years for patients in Cohort B
  • On multivariate analysis, the number of different types of therapy administered to the patients was
  • 3 for the men in Cohort A
  • 5 to 12 for the men in Cohort B
  • Average overall survival was
  • 2.2 years for patients in Cohort A
  • 2.8 years for patients in Cohort B
  • 5-year overall survival was
  • 10 percent for the patients in Cohort A
  • 26 percent for the patients in Cohort B
  • Receptor Tyrosine Kinase Growth Factor Pathways

    Overview and Pharmacotherapy of Prostate Cancer (based on ...

    Multiple RTK growth factor signaling pathways including EGFR,, IGF-1R,, FGFR, PDGFR,, and HGFR/c-MET- pathways have been investigated extensively in prostate cancer progression due to their activation of the PI3K-AKT and RAS-MAPK pathways. Combined loss of PTEN with activation of the RAS-MAPK pathway can cooperate to induce epithelial to mesenchymal transition and metastases. Several clinical trials have been conducted targeting EGFR, including two using lapatinib, one of which was negative, and another that was more encouraging with single agent activity in a subset of patients. A third trial using cetuximab showed significant progression free survival in approximately half of the treated patients. Antibodies against IGF-1R have shown some efficacy in xenografts and in human trials.

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    The Role Of A Multidisciplinary Care Team In Treatment

    Keep in mind that the optimal treatment strategy for mCRPC is different for each person and that its a complicated disease to treat. Thats why its important to assemble a team of doctors and specialists to keep your treatment and you on track.

    Your team should include an experienced urologist, advises Cookson, as well oncologists who are comfortable with the newer treatments and know how to use them.

    A study published in July 2015 in the Journal of Urology agrees, finding that with so many new treatments coming on board, doctors have to juggle a lot of factors when figuring out your best next steps from what kind of symptoms you have to your personal preferences, as well as any other health conditions that may have to be taken into account when coming up with a treatment strategy.

    Its also important for your care team to review the medicines youve already taken for prostate cancer, and plan the sequence of the medicines youll take next. Getting the order right is important because certain drugs can make subsequent treatments more, or less, effective.

    Your care team should also watch you closely to determine whether you have any resistance to any medicines, so that they can make changes quickly if necessary.

    Ideally, your care team should possess expertise in distinct domains of cancer care, such as imaging, chemotherapy, radiation, and surgery, according to a study published in the Annals of Oncology in August 2015.

    Treatment To Lower Androgen Levels From The Adrenal Glands

    LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands, and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Drugs are available that block the formation of androgens made by these cells.

    Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making androgens.

    Abiraterone can be used in men with advanced prostate cancer that is either:

    • High risk
    • Castrate-resistant

    This drug is taken as pills every day. It doesnt stop the testicles from making testosterone, so men who havent had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone needs to be taken during treatment as well to avoid certain side effects.

    Ketoconazole , first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. It’s most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.

    Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid .

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    The Pi3k/akt/mammalian Target Of Rapamycin Pathway

    The PI3K pathway is one of the most critical in human cancer. Various growth factors, including insulin-like growth factor and fibroblast growth factor , regulate this pathway, leading to activation of PI3K and the formation of PIP3. PIP3 activates AKT via phosphorylation and phosphorylated Akt activates multiple molecules involved in cell survival and proliferation, including MDM2, c-myc, GSK3, nuclear factor-B and mTOR. Phosphatase and tensin homolog deleted on chromosome 10 is a lipid phosphatase that functions as the main inhibitor of PI3K/Akt signaling. Genetic alterations of the PI3K signaling pathway occur in 42% and 100% of primary and metastatic prostate cancers, respectively, suggesting this pathway is crucial in the development of CRPC.

    Additional experiments showed that after 7 days of enzalutamide treatment of Ptenloxp/loxp mice, despite decreased AR transcriptional activity the tumors had not significantly regressed and were histologically similar to those before treatment, although the treatment was much more effective in transgenic mice with inducible c-myc. Further studies revealed increased Akt phosphorylation at Ser473 in the Ptenloxp/loxp mice and in LNCaP and LAPC4 AR-positive cells after castration and enzalutamide treatment, respectively. The same treatment did not increase pAkt in PC-3 cells, which are AR negative.

    Treatment By Stage Of Prostate Cancer

    Treating Non-Metastatic Castrate Resistant Prostate Cancer | Ask a Prostate Expert, Mark Scholz, MD

    Different treatments may be recommended for each stage of prostate cancer. Your doctor will recommend a specific treatment plan for you based on the cancers stage and other factors. Detailed descriptions of each type of treatment are provided earlier on this same page. Clinical trials may also be a treatment option for each stage.

    Early-stage prostate cancer

    Early-stage prostate cancer usually grows very slowly and may take years to cause any symptoms or other health problems, if it ever does at all. As a result, active surveillance or watchful waiting may be recommended. Radiation therapy or surgery may also be suggested, as well as treatment in clinical trials. For those with a higher Gleason score, the cancer may be faster growing, so radical prostatectomy and radiation therapy are often recommended. Your doctor will consider your age and general health before recommending a treatment plan.

    ASCO, the American Urological Association, American Society of Radiation Oncology, and the Society of Urologic Oncology recommend that patients with high-risk early-stage prostate cancer that has not spread to other areas of the body should receive radical prostatectomy or radiation therapy with hormonal therapy as standard treatment options.

    Locally advanced prostate cancer

    Watchful waiting may be considered for older adults who are not expected to live for a long time and whose cancer is not causing symptoms or for those who have another, more serious illness.

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    Access And Reimbursement Scenario In Crpc Therapies

    • In mCRPC setting, most of the therapies can secure the positive recommendation given the high unmet need in this particular setting. And for emerging therapies targeting this setting benchmark for comparison would be Xtandi and Zytiga.
    • In nmCRPC setting, access and reimbursement path for newer and as well approved therapies will not a cake walk and similar findings seen in case of Xtandi rejection by NICE for treating hormone-relapsed non-metastatic prostate cancer or nmCRPC.

    Targeting The Androgen Receptor : The Next Step In Prostate Cancer Therapy

    As recently published in the New England Journal of Medicine, Antonarakis and collaborators demonstrated that 20-40% of circulating tumor cells in CRPC patients treated with abiraterone and enzalutamide have ARV7 constitutively active . More importantly, however, they demonstrated in this prospective trial that the subset of men with ARV7 in circulating tumor cells had a significantly lower PSA response rate, shorter progression-free survival and overall survival compared to men without ARV7 expression. This study, our own research , and studies by other groups demonstrate that ARVs are an important mechanism of resistance to newer CRPC agents. Liu et al. demonstrated that AR-V7 was present in a number of prostate cancer cell lines and that it was able to activate the PSA promoter in LNCaP and PC3 cells in the absence of androgen . With the loss of the LBD on the AR as seen in ARV-7, CRPC cell lines overcome the loss of circulating and intratumoral androgens mediated by abiraterone. Loss of the LBD, and concurrent ligand-independent binding of AR to AREâs, is thought to be the underlying mechanism of resistance to enzalutamide. Li et al. demonstrated that knockdown of AR-V limited androgen-independent growth rate of CWR22Rv1 cells and restored responsiveness to anti-androgens .

    Perhaps by targeting the AR and its variants, we may be able to overcome the deficiencies of current CRPC treatments.

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    Androgen Receptor Signaling In The Development Of Castration

    • 1Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, United States
    • 2Departments of Surgery and Urology, Immunobiology & Transplant Science Center, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
    • 3Department of Medicine-Cancer Biology, Weill Cornell Medicine, Cornell University, New York, NY, United States

    Ar Dependent Mechanisms Of Resistance Leading To Crpc

    Treatment of advanced metastatic prostate cancer

    The majority of mechanisms identified leading to castration-resistant are mediated by AR or the androgen axis. As seen in , they can be categorized into five main subsets.

    Androgen receptor-dependent mechanisms of resistance in hormone-naive prostate cancer leading to castration-resistance. wtAR, wild-type androgen receptor ARV, androgen receptor variant mutAR, mutated androgen receptor T, testosterone DHT, dihydrotestosterone SHGB, sex hormone binding globulin.

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    Index Patient : Asymptomatic Non

    One of the first clinical presentations of CRPC occurs in a patient with a rising PSA despite medical or surgical castration. This is typically defined as a patient with a rising PSA and no radiologic evidence of metastatic prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 defines PSA only failure as a rising PSA that is greater than 2ng/mL higher than the nadir the rise has to be at least 25% over nadir, and the rise has to be confirmed by a second PSA at least three weeks later. In addition, the patient is required to have castrate levels of testosterone and no radiographic evidence of metastatic disease.16 These patients represent a relatively common clinical presentation and the earliest clinical manifestation of castration resistance.

    Guideline Statement 1

    Clinicians offer apalutamide or enzalutamide with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease.

    Discussion

    Enzalutamide: Enzalutamide is a novel AR signaling inhibitor. It is a competitive inhibitor of androgen binding and also inhibits nuclear translocation of the AR, DNA binding and coactivator recruitment.18 This drug binds AR with a five- to eight-fold higher affinity than bicalutamide.18

    Guideline Statement 2

    Clinicians may recommend observation with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease who do not want or cannot have one of the standard therapies.

    Analysis Of Crpc Genomes

    Although primary prostate cancers are characterized by genomic translocations that place androgen-responsive promoters such as TMPRSS2 adjacent to ETS-family transcription factors such as ERG, ETV1, ETV5, and ETV4, metastatic prostate cancers can harbor rare gene rearrangements that generate fusions of ubiquitin conjugating enzymes with KRAS. Integrated gene expression and copy number analysis of prostate cancers also indicates that more aggressive prostate cancers have increased copy number alterations relative to less aggressive cancers. Moreover, PI3K-AKT was altered in 100% of metastases, while RAS-RAF signaling was altered in 90% of metastases in this study. Exome sequencing of CRPC has identified several recurrent mutations in transcription factors and epigenetic factors that interact with AR such as FOXA1, MLL2, UTX, and ASXL1.

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    How Will I Know That My Hormone Therapy Is Working

    Doctors cannot predict how long hormone therapy will be effective in suppressing the growth of any individual mans prostate cancer. Therefore, men who take hormone therapy for more than a few months are regularly tested to determine the level of PSA in their blood. An increase in PSA level may indicate that a mans cancer has started growing again. A PSA level that continues to increase while hormone therapy is successfully keeping androgen levels extremely low is an indicator that a mans prostate cancer has become resistant to the hormone therapy that is currently being used.

    Enzalutamide And Androgen Receptor Inhibitors

    Fatigue in men with castration resistant prostate cancer treated with enzalutamide

    In response to the many AR mediated mechanisms of resistance found leading to development of CRPC, there has been development of a new generation of androgen-receptor signaling inhibitors. The main agent in this class is enzalutamide , which has been demonstrated to have a multi-pronged approachâpreventing testosterone binding to AR, AR nuclear translocation, AR binding to DNA, and co-activator recruitment . While the AFFIRM III trial demonstrated a 4.8-month survival benefit over placebo in CRPC patients who had failed docetaxel and the PREVAIL trial demonstrated an overall survival and radiographic progression-free survival over placebo in chemotherapy-naïve CRPC patients , not all the patients benefited from treatmentâa subset of patients continued to progress, indicating that there are significant resistance mechanisms that need to be identified and addressed.

    AR point mutations are also important mechanisms of resistance to enzalutamide, just as in the development of CRPC. The Phe876Leu mutation in the LBD of AR has been reported to make enzalutamide into an agonist of AR, though the clinical relevance of this change has not been documented . Similar effects were noted for the first generation anti-androgens bicalutamide and flutamide.

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