Comparison of Abiraterone and Combined Androgen Blockade Therapy for High-Risk Metastatic Hormone-Sensitive Prostate Cancer: A Propensity Score-Matched Analysis PMC

Flutamide is a type of anti-androgen people use with other medications to treat certain types of prostate cancer. Flutamide binds to the androgen receptors in prostate cancer cells, which blocks androgens from binding to the receptors. This prevents androgens from encouraging prostate cancer cell growth. Lowering androgen levels, or preventing androgens from reaching cancer cells, can help slow down cancer.

  1. Metastatic hormone-sensitive prostate cancer (mHSPC) accounts for up to 5% of patients newly diagnosed with prostate cancer in the United States (3).
  2. Examples include anti-platelet drugs such as clopidogrel, “blood thinners” such as dabigatran/enoxaparin/warfarin, among others.
  3. Mutations in the AR gene prevent androgen receptors from working properly, which makes cells less responsive to androgens or prevents cells from using these hormones at all.
  4. They bind to these receptors so that androgens can’t bind to them.

Measuring average sizes of individual organoids and the organoid forming efficiency further affirmed the inhibitory effects of ENZ, Selinexor, and CX5461 (Fig. 6d, e). The effect of the above inhibitors on PCa growth was further examined using in vivo tissue grafting assays (Fig. 6a). Grafts treated with Selinexor were significantly smaller and weighed less than vehicle-treated samples in both intact and castrated hosts, and CX5461 showed a greater inhibitory effect in castrated hosts than in intact hosts (Fig. 6f, g). Histological analyses showed less differentiated tumor characteristics in vehicle-treated grafts from castrated host in comparison to those from intact hosts (Fig. 6h). Pathological changes similar to ADT-induced tumor regression were exhibited in ENZ-treated grafts from intact hosts, and no tumor lesions appeared in Selinexor or CX5461-treated grafted samples (Fig. 6h).

Cell culture and shRNA lentivirus infection

For that reason, it’s typically reserved for advanced prostate cancer diagnoses. Anti-androgen therapy can help shrink existing tumors as well as slow the rate of new cancerous growth. In its early stages, prostate cancer cells rely on androgens to feed their growth.

About two-thirds of all cases of androgen insensitivity syndrome are inherited from mothers who carry an altered copy of the AR gene on one of their two X chromosomes. The remaining cases result from a new mutation that can occur in the mother’s egg cell before the child is conceived or during early fetal development. If you think you may have abnormal androgen levels, it’s a good idea to speak with your doctor. A blood test can help determine whether you have a deficiency or a surplus of androgens that requires treatment.

Androgens play a role in stimulating cancer cell growth in the prostate. As a result, anti-androgen therapy may sometimes be used to treat prostate cancer, especially if the cancer has spread too far for treatment with surgery or radiation alone. For nuclear pore complex and cellular morphological analyses, prostate tissues were fixed with 4% paraformaldehyde with 2.5% glutaraldehyde, 0.2 M sodium cacodylate buffered at pH 7.4, and 2 mM CaCl2.

Fluorescence images for nuclear pore complex were collected using Zeiss LSM-700 confocal microscope with Zen 2012 Imaging Software. A healthcare professional can help you choose mandrogen plus an anti-androgen that suits your needs and comes with the fewest side effects. Anti-androgens can produce a range of side effects, depending on the dose and type you take.

However, when assigned females experience hair loss that looks similar to “male-pattern balding,” this may be a sign of hyperandrogenism. In those assigned female at birth, androgen hormones are created in fat cells and the ovaries. They are also made in the adrenal glands, which are located above the kidneys and are responsible for releasing various hormones. Alternative medications can increase testosterone levels without negatively affecting male fertility and may help improve male fertility.

People with complete androgen insensitivity syndrome also have sparse or absent hair in the pubic area and under the arms. Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. People with this condition are genetically male, with one X chromosome and one Y chromosome in each cell.

A randomized Phase III trial of enzalutamide and pembrolizumab in patients with mCRPC (KEYNOTE-641) was discontinued due to futility after an interim analysis. Despite preclinical data suggesting a potential relationship between AR antagonism and response to immune checkpoint blockade, a prospective clinical trial did not support these findings. In preclinical prostate cancer models, supraphysiologic testosterone inhibited cell cycle progression, induced double-strand DNA breaks and genomic rearrangements, and downregulated AR as well as constitutively active AR splice variants5,6,7,8,9,10,11,12,13. Bipolar androgen therapy (BAT), whereby serum testosterone levels are rapidly driven to a supraphysiologic range followed by a return to near-castrate levels over 28-day cycles, is a treatment paradigm for patients with mCRPC developed by our group3. Multiple clinical trials have shown BAT to be well tolerated (not resulting in disease flares) with preliminary clinical activity14,15,16,17,18.

How to Naturally Decrease High Androgens

While the expression of cytoplasmic and nuclear β-catenin appeared in Adeno-PCa cells, prominent nuclear β-catenin expression was observed in both Solid-PCa and lung metastatic tumor cells of TripleTg mice (Fig. 5a). Co-IF analyses further showed that elevated expression of SP1 was overlaid with extensive stabilized β-catenin expression in Solid-PCa cells but not in Adeno-PCa cells of TripleTg mice, and PCa cells of DoubleTg mice (Fig. 5a, b and Supplementary Fig. 5f). Moreover, predominant peri-nuclear staining of XPO1, overlaying with the nuclear SP1, was specifically seen in Solid-PCa cells but not in Adeno-PCa cells and in PCa cells of DoubleTg mice (Fig. 5a, b and Supplementary Fig. 5f).

Multiplex IHC and image analysis

However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC)2,4. To inhibit the re-activation of AR-promoted tumor growth via residual androgens7, more potent AR antagonists and inhibitors for blocking androgen synthesis have been developed in recent years8. While these second-generation antagonists/inhibitors showed some effectiveness clinically, emerging evidence has shown that they also induced more diverse CRPC phenotypes9.

Anti-androgens work by blocking androgens from binding to androgen receptors in prostate cancer cells. This starves the cancer cells of the androgens they need to grow. Complete androgen insensitivity syndrome occurs when the body cannot use androgens at all. People with this form of the condition have the external sex characteristics of females, but do not have a uterus and therefore do not menstruate and are unable to conceive a child (infertile).

Whereas these data need to be validated in relevant human samples and cell lines, they suggest a potential combinational therapeutic strategy with ADT for future treatment of advanced PCa. Additionally, observations of increased XPO1 expression in castrated TripleTg mouse PCa samples and clinical samples of ABI- and ENZ-treated patients further support the promotional role of XPO1 in PCa progression, hormone refractoriness, and DNPC development. Therefore, more studies using biologically relevant human DNPC samples and cell lines warrant further validation our data from the above GEMMs to fully understand the pathogenesis of DNPC. Identifying elevated expression of XPO1 in poorly differentiated Solid-PCa cells in TripleTg mice suggests a regulatory role of Wnt/β-catenin signaling in PCa progression and DNPC development. It has been shown that SP1 regulates Xpo1 transcription30 and β-catenin enhances SP1 transcriptional activity through directly interacting and stabilizing the SP1 protein31. Using IHC approaches, we first assessed the expression of stabilized β-catenin on SP1 and XPO1 expression in mouse PCa samples.

Uses of androgen therapies

You may want to see a dermatologist, a doctor who specializes in treating skin, hair, and nails. The dermatologist may prescribe you treatments that are more effective than over-the-counter options. Some may choose to directly remove unwanted hair growth, but keep in mind that most of these options will only work temporarily.

Elevated expression of MYC, a master regulator of ribosome biogenesis28, has been observed in Solid-PCa cells (Fig. 4k). Accordingly, elevated expression of RPs and Eif4a1 was also detected in both prostate primary and metastatic tumor cells, aligning with upregulated XPO1, HGF/MET, and Wnt/β-catenin downstream target expression. In this study, we also observed the effect of XPO1 inhibition on reducing both global translation and decreasing nucleolar size and number in PCa cells derived from TripleTg mice (Supplementary Fig. 7a–d). These data suggest the important role of XPO1 in facilitating rRNAs, RPs, and assembly factors in ribosomal biogenesis and protein synthesis during tumor growth and progression44. High-level ribosomal protein amplifications occur frequently in metastatic breast cancer and CRPC samples45,46, and dual RP inhibitors have shown an inhibitory effect on the growth of patient-derived xenograft (PDX) from CRPC patients46. Additionally, reduced AR content increases the assembly of the EIF4F translation initiation complex, thereby promoting cell proliferation47.


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