This comprehensive literature review delves into the multifaceted roles of RNA-binding motif protein 3 (RBM3) in cellular processes, disease pathogenesis, and therapeutic potential. RBM3 has been implicated in shaping cell morphology, synaptic protection in neurodegenerative conditions, and regulating gene expression through binding to specific RNA sequences. In cancer, RBM3 exhibits contrasting effects, influencing cell proliferation, tumorigenic potential, and RNA splicing. Clinical studies suggest RBM3 as a predictive biomarker in chemotherapy response for muscle-invasive bladder cancer. Despite promising therapeutic implications in neuroprotection and cancer, challenges persist in understanding the regulatory mechanisms and clinical behavior of RBM3. Further research is warranted to elucidate the molecular mechanisms underlying RBM3’s diverse functions and its significance as a potential target for personalized medicine in cancer therapy. This review underscores the pivotal role of RBPs, particularly RBM3, in disease progression and highlights the need for continued investigation to harness their therapeutic potential effectively. This review evaluates evidence available through December 2025, with particular emphasis on studies published between 2010 and 2025.

Solid tumors as well as leukemias and lymphomas show striking changes in nuclear structure including nuclear size and shape, the number and size of nucleoli, and chromatin texture. These alterations have been used in cancer diagnosis and might be related to the altered functional properties of cancer cells. The nuclear matrix (NM) represents the structural composition of the nucleus and consists of nuclear lamins and pore complexes, an internal ribonucleic protein network, and residual nucleoli. In the nuclear microenvironment, the NM is associated with multi-protein complexes, such as basal transcription factors, signaling proteins, histone-modifying factors, and chromatin remodeling machinery directly or indirectly through scaffolding proteins. Therefore, alterations in the composition of NM could result in altered DNA topology and changes in the interaction of various genes, which could then participate in a cascade of the cancer process. Using an androgen-sensitive prostate cancer cell line, LNCaP, and its androgen-independent derivative, LN96, conventional 2D-proteomic analysis of the NM proteins revealed that purine-rich element binding protein alpha (PURα) was detected in the NM proteins and differentially expressed between the cell lines. In this article, we will review the potential role of the molecule in prostate cancer.

Supplementary Figure 4 - PDF file 146K, mRNA expression of Cyclin D1 was evaluated in PC3 cells (A) and DU145 cells (B) that formed colonies in soft agar or those grew in the regular 2D culture condition by qRT-PCR. Values are mean s.d. (n = 4). (C), PC3 cells were cultured under 32˚C for 0 hr to 144 hr, and mRNA level of cyclin D1 was detected by qRT-PCR. Values are mean s.d. (n = 4). (D) Over-expression of CD44 variant and standard construct. LNCaP cells were transfected with pLenti-III-CD44s (CD44s), pLenti-III-CD44v8-v10 (CD44v8-10) or empty vector. After 48 hr of transfection, cells were collected and the expression of mRNA and protein of CD44 were detected by RT-PCR and Western blot, respectively. Data are mean s.d. (n = 3), *P < 0.05

Supplementary Figures and Tables

Supplementary Figures S1-S2 from Evaluation of Colon Cancer–Specific Antigen 2 as a Potential Serum Marker for Colorectal Cancer

Supplementary Figure 2 - PDF file 68K, (A), expression of cancer-related miRNAs was detected in the PC3-RBM3 and PC3-GFP clones using a cancer-specific miRNA PCR array. Left panel, selected miRNAs whose expression levels differed more than 1.5 fold in the clone R#1 compared to G#1. Red bars, differentiation-related miRNAs; black bars, other cancer-related miRNAs. Right panel, the up-regulation of miR-9 in PC3-RBM3 clones was validated by RT-PCR. Values are mean s.d. (n = 3), *P < 0.05. (B), left panel, β3-tubulin expression was detected by Western blot in PC3-GFP and PC3-RBM3 clones. Right panel, quantitative evaluation of protein levels of β3-tubulin. Values are mean s.d. (n = 3), *P < 0.05. (C), the immunohistochemical staining of RBM3 and β3-tubulin in the nerve fibers observed in human prostate tissue. Upper panels, low magnification; lower panels, high magnification. Scale bars, 100 m. In all panels: G#1, PC3-GFP-clone #1; G#2, PC3-GFP-clone #2; R#1, PC3-RBM3-clone #1; R#6, PC3-RBM3-clone #6.expression of CDH2 in PC3-GFP and PC3-RBM3 clones

Supplementary Figure 3 - PDF file 244K, (A), CD44 variant mRNAs were amplified by PCR using the general primers c13 and hs3'. The PCR products at size of 650 bp and 250 bp were cut and subjected to direct DNA sequencing. The numbers in the block are exons number of CD44. N, negative control; G#1, PC3-GFP-clone #1. (B), schematic diagram of designing siRNAs specific to CD 44 variant exons v8-v10 (siC1, siC2) and primers specific to CD44v8-v10 (CD44v) or standard CD44 (CD44s). Primers c13 and hs3' can amplify both CD44s and CD44v. Primers p1 and p2 can only amplify CD44v8-v10, while primers p3 and p4 are specific to standard CD44s. Primer hs5' is the outside primer of the nest PCR. (C), the specificity of siRNAs targeting for CD44v8-v10. Variant exon-specific PCR was performed using primer p1 and p2. CD44s was amplified using CD44 standard-specific primer p3 and p4. siN, non-target siRNA. Data are mean s.d. (n = 3), *P < 0.05. (D), the efficiency of siRNA pool targeting RBM3. Cells were treated with siRBM3 or non-targeting siRNA (siN) for 48 hr. The expression of mRNA and protein of CD44 were detected by RT-PCR and Western blot, respectively. R#1, PC3-RBM3-clone #1; R#6, PC3-RBM3-clone #6. Data are mean s.d. (n = 3), *P < 0.05

Supplementary Table 2 - PDF file 33K, Calculated size of PCR products for CD44 splicing variants

Supplementary Table from A Phase Ib/II Study of Sabizabulin, a Novel Oral Cytoskeleton Disruptor, in Men with Metastatic Castration-resistant Prostate Cancer with Progression on an Androgen Receptor–targeting Agent

INTRODUCTION:The availability of oral therapies for advanced prostate cancer allows urologists to continue to care for their patients who develop castration resistance. We compared the prescribing practices of urologists and medical oncologists in treating this patient population.METHODS:The Medicare Part D Prescribers data sets were utilized to identify urologists and medical oncologists who prescribed enzalutamide and/or abiraterone from 2013 to 2019. Each physician was assigned to one of 2 groups: enzalutamide prescriber (physicians that wrote more 30-day prescriptions for enzalutamide than abiraterone) or abiraterone prescriber (opposite). We ran a generalized linear regression to determine factors influencing prescribing preference.RESULTS:In 2019, 4,664 physicians met our inclusion criteria: 23.4% (1,090/4,664) urologists and 76.6% (3,574/4,664) medical oncologists. Urologists were more likely to be enzalutamide prescribers (OR 4.91, CI 4.22-5.74, P < .001) and this held in all regions. Urologists with greater than 60 prescriptions of either drug were not shown to be enzalutamide prescribers (OR 1.18, CI 0.83-1.66, P = .349); 37.9% (5,702/15,062) of abiraterone fills by urologists were for generic compared to 62.5% (57,949/92,741) of abiraterone fills by medical oncologists.CONCLUSIONS:There are dramatic prescribing differences between urologists and medical oncologists. A greater understanding of these differences is a health care imperative.

<p>Supplementary Table 1 - PDF file 43K, mRNA expression of stem cell-related gene using a Stem Cell PCR array</p>

Supplementary Figures 1-2 from Initial Analyses of Colon Cancer–Specific Antigen (CCSA)-3 and CCSA-4 as Colorectal Cancer–Associated Serum Markers

Supplementary documents - PDF file 122K, Supplementary methods and supplementary figures legends

Supplementary Figure 1 - PDF file 202K, (A), expression of RBM3 in different human tissues. Data are mean s.d. (n = 3). (B), expression of CIRBP in CD133+ and CD133- PrEC cells. mRNA levels of RBM3 and CIRBP was determined by RT-PCR. Data are mean s.d. (n = 4). (C), mRNA levels of RBM3 were detected in the PC3-GFP and PC3-RBM3 clones by RT-PCR. Data are mean s.d. (n = 3), *P < 0.05. (D), RBM3 protein was detected in both cytoplasmic (Cyto) and nuclear (Nu) components of PC3-GFP and PC3-RBM3 clones. Tubulin and Lammn A/C were used as loading controls for cytoplasmic and nuclear fractions, respectively. In all panels: G#1, PC3-GFP-clone #1; G#2, PC3-GFP-clone #2; R#1, PC3-RBM3-clone #1; R#6, PC3-RBM3-clone #6

Supplementary Figure 5 - PDF file 104K, (A), mRNA levels of CD44v8-v10 (CD44v) were determined in human normal and prostate cancer tissues by RT-PCR. Normal, normal prostate tissue (n = 19); OC-PCa, organ-confined prostate cancer (n = 79); Met-PCa, metastatic prostate cancer (n = 23). (B), mRNA levels of CD44v were compared between patients with recurrent PCa (Rec, n = 44) and those without recurrent disease (Non-rec, n = 30). (C) and (D), mRNA levels of standard CD44 (CD44s) (C) or CD44v (D) were compared between patients with low grade PCa (Gleason score 6, n = 21) and those with high grade disease (Gleason score > 6, n = 53). All experiments were repeated three times. Bars indicate median values

Abstract Purpose: Sabizabulin, an oral cytoskeleton disruptor, was tested in a phase Ib/II clinical study in men with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: The phase Ib portion utilized a 3+3 design with escalating daily oral doses of 4.5–81 mg and increasing schedule in 39 patients with mCRPC treated with one or more androgen receptor–targeting agents. Prior taxane chemotherapy was allowed. The phase II portion tested a daily dose of 63 mg in 41 patients with no prior chemotherapy. Efficacy was assessed using PCWG3 and RECIST 1.1 criteria. Results: The MTD was not defined in the phase Ib and the recommended phase II dose was set at 63 mg/day. The most common adverse events (>10% frequency) at the 63 mg oral daily dosing (combined phase Ib/II data) were predominantly grade 1–2 events. Grade ≥3 events included diarrhea (7.4%), fatigue (5.6%), and alanine aminotransferase/aspartate aminotransferase elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle of 63 mg or higher included objective response rate in 6 of 29 (20.7%) patients with measurable disease (1 complete, 5 partial) and 14 of 48 (29.2%) patients had PSA declines. The Kaplan–Meier median radiographic progression-free survival was estimated to be 11.4 months (n = 55). Durable responses lasting >2.75 years were observed. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with preliminary antitumor activity. These data support the ongoing phase III VERACITY trial of sabizabulin in men with mCRPC.

You have accessJournal of UrologyCME1 May 2022MP27-15 SABIZABULIN HAS BOTH CYTOTOXIC AND CYTOSTATIC ACTIVITY IN PHASE 1B/2 CLINICAL OF MEN WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER WHO PROGRESSED ON ANDROGEN RECEPTOR TARGETING AGENTS Mark Markowski, Mario Eisenberger, Christopher Pieczonka, Robert Getzenberg, Domingo Rodriguez, K. Gary Barnette, MItchell Steiner, Daniel Saltzstein, Emmanuel Antonarakis, and Ronald Tutrone Mark MarkowskiMark Markowski More articles by this author , Mario EisenbergerMario Eisenberger More articles by this author , Christopher PieczonkaChristopher Pieczonka More articles by this author , Robert GetzenbergRobert Getzenberg More articles by this author , Domingo RodriguezDomingo Rodriguez More articles by this author , K. Gary BarnetteK. Gary Barnette More articles by this author , MItchell SteinerMItchell Steiner More articles by this author , Daniel SaltzsteinDaniel Saltzstein More articles by this author , Emmanuel AntonarakisEmmanuel Antonarakis More articles by this author , and Ronald TutroneRonald Tutrone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002570.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents (ARTAs). METHODS: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose (RP2D) of 63 mg daily. Based upon the Phase 1b/2 data, sabizabulin appears to have both cytotoxic and cytostatic activity. A analysis was conducted evaluating the best clinical response (BCR) defined as either an objective response assessed by PCWG3 criteria and/or stable disease defined as > 5 cycles ( > 15 weeks) of continuous treatment. RESULTS: Of the combined 80 patients in the Phase 1b/2 portions of the study, the BCR was 37.5% (30/80) and 5 of the responders remain on study with the longest being treated for more than 30 months. Of the patients with measurable disease at study entry, the BCR was 59% (17/29). Prior to study entry, 11/30 (37%) of those with a BCR had previously been treated with and subsequently progressed on a minimum of 2 ARTAs. The remaining 19/30 (63%) had progressed on a single ARTA agent. 11 (37%) were previously treated with enzalutamide or apalutamide and 8 (27%) with abiraterone as single agents. 8 (27%) received enzalutamide and abiraterone and 3 (10%) patients received more than two ARTAs. As described previously, the safety profile continues to be favorable with no clinically relevant neutropenia or neurotoxicity and the most commonly observed adverse events being gastrointestinal in nature. CONCLUSIONS: In this analysis, sabizabulin has demonstrated not only cytotoxic, but also significant cytostatic activity with similar responses in men that have progressed on a single or multiple ARTA agents. Sabizabulin is a novel agent with the potential provide men with mCRPC a well-tolerated chronic treatment cytostatic option after progressing on an ARTA and is being tested in the open Phase 3 VERACITY trial. Source of Funding: Veru Inc © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e456 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mark Markowski More articles by this author Mario Eisenberger More articles by this author Christopher Pieczonka More articles by this author Robert Getzenberg More articles by this author Domingo Rodriguez More articles by this author K. Gary Barnette More articles by this author MItchell Steiner More articles by this author Daniel Saltzstein More articles by this author Emmanuel Antonarakis More articles by this author Ronald Tutrone More articles by this author Expand All Advertisement PDF DownloadLoading ...

5049 Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents. Methods: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose of 63 mg daily. Efficacy was assessed by bone/CT scans. A final analysis of the safety and efficacy data including the primary endpoint, the median progression-free survival was conducted. Results: Although the MTD was not reached in the Phase 1b, the recommended Phase 2 dose was set at 63 mg/day to maximize GI tolerability. The most common adverse events (> 10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 data) were predominantly Grade 1-2. Grade ³3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle (21 days) of 63 mg or higher (n = 55) included an objective response rate of 6/29 (20.7%) in patients with measurable disease (1 complete, 5 partial). 14/48 (29.2%) of the patients had PSA declines. The Kaplan-Meier median radiographic progression-free survival was estimated to be 11.4 months (95% C.I. 29.63-65.79) (n = 55). Durable responses lasting > 2.75 years were observed with 14.5% (8/55) demonstrating a response greater than 12 months. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent. Clinical trial information: NCT03752099.

Abstract Targeting the androgen receptor (AR) may be the next important endocrine therapy for women with advanced breast cancer. AR is the most abundantly expressed steroid receptor in breast cancer and has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective nonsteroidal agonist that activates the AR in breast cancer. Enobosarm has an extensive clinical experience in 25 clinical trials and 1,450 dosed subjects including in breast cancer where three Phase 2 studies have been conducted two of which were in women (158 subjects) who had AR+/ER+/HER2- metastatic breast cancer (MBC).The larger Phase 2 clinical trial (G200802) evaluated 9mg and 18mg enobosarm daily oral dosing in 136 women with ER+/HER2- MBC who previously responded to endocrine treatment. Patients were heavily pretreated having progressed on an average of 3 endocrine treatments and 90% had prior chemotherapy. Enobosarm showed efficacy activity in the overall study with a clinical benefit rate at 6 months of 32% (95% CI: 19.5%,46.7%) for the 9 mg and 29% (95% CI: 17.1%,43.1%) for the 18 mg evaluable cohorts. Quality of life assessments showed significant improvement from baseline for both enobosarm cohorts (p=0.002). Enobosarm was well tolerated at both doses. In a post-hoc analysis in all patients (9mg and 18mg) with known AR status and measurable disease (n=84), AR expression in breast. cancer tissue (%AR nuclei staining) correlated with efficacy outcomes. When comparing AR nuclei staining ≥40% (n=47) compared to patients with an AR nuclei staining <40% (n=37): 1) Clinical benefit rate at 6 months was 52% for AR ≥40% and 14% for AR <40% (p<0.0004); 2) Overall response rate (ORR) was 34% for AR ≥40% and 2.7% for AR <40% (p<0.0003; 3) Radiographic was 5.47 months for AR ≥40% and 2.72 months for AR <40% (p<0.001). The ARTEST trial is a Phase 3 multicenter, international randomized, open-label, two treatment arm, efficacy and safety study. Approximately, 210 subjects with AR+ ER+ HER2- MBC and with AR nuclei staining ≥40% will be randomized 1:1 to either enobosarm 9mg oral daily dose or an active comparator (either exemestane ± everolimus or selective estrogen receptor modulator; physician’s choice). Subjects will be treated until disease progression is observed or an unacceptable adverse event is observed. The primary endpoint of the study is imaging based progression free survival as measured by RECIST 1.1. The secondary objectives/endpoints on this study include the ORR, duration of response, overall survival, and change from baseline in Short Physical Performance Battery (SPPB). The study is planned to begin enrollment in Q3 2021. Citation Format: Adam Brufsky, Hannah Linden, Hope Rugo, Charles Vogel, Joyce A O'Shaughnessy, Robert H Getzenberg, K. Gary Barnette, Domingo Rodriguez, Mitchell S Steiner, Erica Mayer. Randomized, multicenter, international phase 3 ARTEST study to evaluate the efficacy and safety of enobosarm versus active control for the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who progressed on a nonsteroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-17-01.