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Cell Chemical Biology Feb 2024PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a...
PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.
Topics: Male; Humans; Drug Resistance, Neoplasm; Prostatic Neoplasms; Phosphorylation; Apoptosis; Cell Proliferation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-pim-1
PubMed: 38016478
DOI: 10.1016/j.chembiol.2023.10.023 -
Strahlentherapie Und Onkologie : Organ... Mar 2024For prostate cancer, the role of elective nodal irradiation (ENI) for cN0 or pN0 patients has been under discussion for years. Considering the recent publications of... (Review)
Review
Prostate cancer and elective nodal radiation therapy for cN0 and pN0-a never ending story? : Recommendations from the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO).
For prostate cancer, the role of elective nodal irradiation (ENI) for cN0 or pN0 patients has been under discussion for years. Considering the recent publications of randomized controlled trials, the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO) aimed to discuss and summarize the current literature. Modern trials have been recently published for both treatment-naïve patients (POP-RT trial) and patients after surgery (SPPORT trial). Although there are more reliable data to date, we identified several limitations currently complicating the definitions of general recommendations. For patients with cN0 (conventional or PSMA-PET staging) undergoing definitive radiotherapy, only men with high-risk factors for nodal involvement (e.g., cT3a, GS ≥ 8, PSA ≥ 20 ng/ml) seem to benefit from ENI. For biochemical relapse in the postoperative situation (pN0) and no PSMA imaging, ENI may be added to patients with risk factors according to the SPPORT trial (e.g., GS ≥ 8; PSA > 0.7 ng/ml). If PSMA-PET/CT is negative, ENI may be offered for selected men with high-risk factors as an individual treatment approach.
Topics: Male; Humans; Positron Emission Tomography Computed Tomography; Prostate-Specific Antigen; Radiation Oncology; Neoplasm Recurrence, Local; Prostatic Neoplasms
PubMed: 38273135
DOI: 10.1007/s00066-023-02193-4 -
Radiation Oncology (London, England) Aug 2023Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to...
BACKGROUND
Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach.
METHODS
A retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET.
RESULTS
103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures.
CONCLUSION
PSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.
Topics: Male; Humans; Prostatic Neoplasms; Treatment Outcome; Prostate-Specific Antigen; Androgen Antagonists; Retrospective Studies; Radiosurgery; Neoplasm Recurrence, Local; Positron-Emission Tomography; Positron Emission Tomography Computed Tomography
PubMed: 37528487
DOI: 10.1186/s13014-023-02302-8 -
Molecular Cancer Research : MCR Dec 2023The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links...
UNLABELLED
The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in prostate cancer cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at a steady state in asynchronously growing prostate cancer cells.
IMPLICATIONS
Our data indicate that the clinical benefit of combining ADT with RT is not due to direct AR regulation of DDR gene transcription, and that the field needs to consider alternative mechanisms for this clinical benefit.
Topics: Male; Humans; Receptors, Androgen; Prostatic Neoplasms; Androgen Antagonists; Cell Line, Tumor; DNA Damage; Prostatic Neoplasms, Castration-Resistant
PubMed: 37698543
DOI: 10.1158/1541-7786.MCR-23-0358 -
Cancer Imaging : the Official... Nov 2023To assess the effect of preoperative MRI with standardized Prostate Imaging-Reporting and Data System (PI-RADS) assessment on pathological outcomes in prostate cancer...
OBJECTIVE
To assess the effect of preoperative MRI with standardized Prostate Imaging-Reporting and Data System (PI-RADS) assessment on pathological outcomes in prostate cancer (PCa) patients who underwent radical prostatectomy (RP).
PATIENTS AND METHODS
This retrospective cohort study included patients who had undergone prostate MRI and subsequent RP for PCa between January 2017 and December 2022. The patients were divided into the PI-RADS group and the non-PI-RADS group according to evaluation scheme of presurgery MRI. The preoperative characteristics and postoperative outcomes were retrieved and analyzed. The pathological outcomes included pathological T stage (pT2 vs. pT3-4) and positive surgical margins (PSMs). Patients were further stratified according to statistically significant preoperative variables to assess the difference in pathological outcomes. A propensity score matching based on the above preoperative characteristics was additionally performed.
RESULTS
A total of 380 patients were included in this study, with 201 patients in the PI-RADS group and 179 in the non-PI-RADS group. The two groups had similar preoperative characteristics, except for clinical T stage (cT). As for pathological outcomes, the PI-RADS group showed a significantly lower percentage of pT3-4 (21.4% vs. 48.0%, p < 0.001), a lower percentage of PSMs (31.3% vs. 40.9%, p = 0.055), and a higher concordance between the cT and pT (79.1% vs. 64.8%, p = 0.003). The PI-RADS group also showed a lower proportion of pT3-4 (p < 0.001) in the cT1-2 subgroup and the cohort after propensity score matching. The PSM rate of cT3 patients was reduced by 39.2% in the PI-RADS group but without statistical significance (p = 0.089).
CONCLUSIONS
Preoperative MRI with standardized PI-RADS assessment could benefit the decision-making of patients by reducing the rate of pathologically confirmed non-organ-confined PCa after RP and slightly reducing the PSM rate compared with non-PI-RADS assessment.
Topics: Male; Humans; Prostate; Prostatic Neoplasms; Magnetic Resonance Imaging; Retrospective Studies; Prostatectomy; Neoplasm Grading; Margins of Excision
PubMed: 38008745
DOI: 10.1186/s40644-023-00619-x -
Molecular Cancer Therapeutics Oct 2023Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we...
Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPC) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. Here, we investigated the antitumor effects of compound MPC309, a trivalent display of ethisterone conjugated to a peptoid oligomer backbone that binds to the AR with nanomolar affinity. MPC309 exhibited potent antiproliferative effects on various enzalutamide-resistant prostate cancer models, including those with AR splice variants, ligand-binding mutations, and noncanonical AR gene expression programs, as well as mouse prostate organoids harboring defined genetic alterations that mimic lethal human prostate cancer subtypes. MPC309 is taken up by cells through macropinocytosis, an endocytic process more prevalent in cancer cells than in normal ones, thus providing an opportunity to target tumors selectively. MPC309 triggers a distinct AR transcriptome compared with DHT and enzalutamide, a clinically used antiandrogen. Specifically, MPC309 enhances the expression of differentiation genes while reducing the expression of genes needed for cell division and metabolism. Mechanistically, MPC309 increases AR chromatin occupancy and alters AR interactions with coregulatory proteins in a pattern distinct from DHT. In xenograft studies, MPC309 produced significantly greater tumor suppression than enzalutamide. Altogether, MPC309 represents a promising new AR modulator that can combat resistant disease by promoting an AR antiproliferative gene expression program.
Topics: Male; Animals; Mice; Humans; Receptors, Androgen; Peptoids; Ligands; Ethisterone; Cell Line, Tumor; Drug Resistance, Neoplasm; Prostatic Neoplasms; Nitriles; Androgen Receptor Antagonists; Prostatic Neoplasms, Castration-Resistant
PubMed: 37486978
DOI: 10.1158/1535-7163.MCT-23-0196 -
Pharmacological Research Aug 2023Prostate carcinoma is a malignant situation that arises from genomic alterations in the prostate, leading to changes in tumorigenesis. The NF-κB pathway modulates... (Review)
Review
Prostate carcinoma is a malignant situation that arises from genomic alterations in the prostate, leading to changes in tumorigenesis. The NF-κB pathway modulates various biological mechanisms, including inflammation and immune responses. Dysregulation of NF-κB promotes carcinogenesis, including increased proliferation, invasion, and therapy resistance. As an incurable disease globally, prostate cancer is a significant health concern, and research into genetic mutations and NF-κB function has the efficacy to facilitate the introduction of novel therapies. NF-κB upregulation is observed during prostate cancer progression, resulting in increased cell cycle progression and proliferation rates. Additionally, NF-κB endorses resistance to cell death and enhances the capacity for metastasis, particularly bone metastasis. Overexpression of NF-κB triggers chemoresistance and radio-resistance, and inhibition of NF-κB by anti-tumor compounds can reduce cancer progression. Interestingly, non-coding RNA transcripts can regulate NF-κB level and its nuclear transfer, offering a potential avenue for modulating prostate cancer progression.
Topics: Male; Humans; NF-kappa B; Prostatic Neoplasms; Bone Neoplasms; Carcinogenesis; Mutation; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 37075872
DOI: 10.1016/j.phrs.2023.106775 -
Prostate Cancer and Prostatic Diseases Jun 2024Biochemical recurrence (BCR) following primary interventional treatment occurs in approximately one-third of patients with prostate cancer (PCa). Next-generation imaging... (Review)
Review
BACKGROUND
Biochemical recurrence (BCR) following primary interventional treatment occurs in approximately one-third of patients with prostate cancer (PCa). Next-generation imaging (NGI) can identify local and metastatic recurrence with greater sensitivity than conventional imaging, potentially allowing for more effective interventions. This narrative review examines the current clinical evidence on the utility of NGI for patients with BCR.
METHODS
A search of PubMed was conducted to identify relevant publications on NGI applied to BCR. Given other relevant recent reviews on the topic, this review focused on papers published between January 2018 to May 2023.
RESULTS
NGI technologies, including positron emission tomography (PET) radiotracers and multiparametric magnetic resonance imaging, have demonstrated increased sensitivity and selectivity for diagnosing BCR at prostate-specific antigen (PSA) concentrations <2.0 ng/ml. Detection rates range between 46% and 50%, with decreasing PSA levels for choline (1-3 ng/ml), fluciclovine (0.5-1 ng/ml), and prostate-specific membrane antigen (0.2-0.49 ng/ml) PET radiotracers. Expert working groups and European and US medical societies recommend NGI for patients with BCR.
CONCLUSIONS
Available data support the improved detection performance and selectivity of NGI modalities versus conventional imaging techniques; however, limited clinical evidence exists demonstrating the application of NGI to treatment decision-making and its impact on patient outcomes. The emergence of NGI and displacement of conventional imaging may require a reexamination of the current definitions of BCR, altering our understanding of early recurrence. Redefining the BCR disease state by formalizing the role of NGI in patient management decisions will facilitate greater alignment across research efforts and better reflect the published literature.
Topics: Humans; Male; Prostatic Neoplasms; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Positron-Emission Tomography; Multiparametric Magnetic Resonance Imaging; Biomarkers, Tumor
PubMed: 37679601
DOI: 10.1038/s41391-023-00711-0 -
Cancer Gene Therapy Oct 2023Androgen deprivation therapy (ADT) is the standard care for advanced prostate cancer (PCa) patients. Unfortunately, although tumors respond well initially, they enter...
Androgen deprivation therapy (ADT) is the standard care for advanced prostate cancer (PCa) patients. Unfortunately, although tumors respond well initially, they enter dormancy and eventually progress to fatal/incurable castration-resistant prostate cancer (CRPC). B7-H3 is a promising new target for PCa immunotherapy. CD276 (B7-H3) gene has a presumptive androgen receptor (AR) binding site, suggesting potential AR regulation. However, the relationship between B7-H3 and AR is controversial. Meanwhile, the expression pattern of B7-H3 following ADT and during CRPC progression is largely unknown, but critically important for identifying patients and determining the optimal timing of B7-H3 targeting immunotherapy. In this study, we performed a longitudinal study using our unique PCa patient-derived xenograft (PDX) models and assessed B7-H3 expression during post-ADT disease progression. We further validated our findings at the clinical level in PCa patient samples. We found that B7-H3 expression was negatively regulated by AR during the early phase of ADT treatment, but positively associated with PCa proliferation during the remainder of disease progression. Our findings suggest its use as a biomarker for diagnosis, prognosis, and ADT treatment response, and the potential of combining ADT and B7-H3 targeting immunotherapy for hormone-naïve PCa treatment to prevent fatal CRPC relapse.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Longitudinal Studies; Disease Progression; Neoplasm Recurrence, Local; Receptors, Androgen; Transcription Factors; Hormones; B7 Antigens
PubMed: 37452083
DOI: 10.1038/s41417-023-00644-9 -
The Quarterly Journal of Nuclear... Jun 2024
Topics: Humans; Prostatic Neoplasms; Nuclear Medicine; Male
PubMed: 38860272
DOI: 10.23736/S1824-4785.24.03578-7