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1.
Mol Cancer Ther ; 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38894678

RESUMEN

Polo-like kinase 1 (PLK1) inhibitors have had limited antitumor efficacy as single agents, and a focus of current efforts is on combination therapies. We initially confirmed that the PLK1 specific inhibitor onvansertib (ONV) could enhance responses to a PARP inhibitor (olaparib) in prostate cancer xenografts. To identify more effective combinations we screened a library of bioactive compounds for efficacy in combination with ONV in LNCaP prostate cancer cells, which identified a series of compounds including multiple AKT inhibitors. We confirmed in vitro synergy between ONV and the AKT inhibitor ipatasertib (IPA) and found that the combination increased apoptosis. Mechanistic studies showed that ONV increased expression of the anti-apoptotic protein SURVIVIN, and that this was mitigated by IPA. Studies in three PTEN deficient prostate cancer xenograft models showed that co-treatment with IPA and ONV led to significant tumor growth inhibition compared to monotherapies. Together these in vitro and in vivo studies demonstrate that the efficacy of PLK1 antagonists can be enhanced by PARP or AKT inhibition, and support further development of these combination therapies.

2.
J Clin Oncol ; : JCO2400279, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38754067

RESUMEN

What is most important to patients with BCR prostate cancer? Metastasis-free versus treatment-free survival.

3.
Cell Rep ; 43(5): 114143, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38676924

RESUMEN

Cellular retinaldehyde-binding protein (CRALBP) supports production of 11-cis-retinaldehyde and its delivery to photoreceptors. It is found in the retinal pigment epithelium (RPE) and Müller glia (MG), but the relative functional importance of these two cellular pools is debated. Here, we report RPE- and MG-specific CRALBP knockout (KO) mice and examine their photoreceptor and visual cycle function. Bulk visual chromophore regeneration in RPE-KO mice is 15-fold slower than in controls, accounting for their delayed rod dark adaptation and protection against retinal phototoxicity, whereas MG-KO mice have normal bulk visual chromophore regeneration and retinal light damage susceptibility. Cone pigment regeneration is significantly impaired in RPE-KO mice but mildly affected in MG-KO mice, disclosing an unexpectedly strong reliance of cone photoreceptors on the RPE-based visual cycle. These data reveal a dominant role for RPE-CRALBP in supporting rod and cone function and highlight the importance of RPE cell targeting for CRALBP gene therapies.


Asunto(s)
Proteínas Portadoras , Ratones Noqueados , Células Fotorreceptoras Retinianas Conos , Epitelio Pigmentado de la Retina , Animales , Ratones , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Células Ependimogliales/metabolismo , Ratones Endogámicos C57BL , Células Fotorreceptoras Retinianas Conos/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Pigmentos Retinianos/metabolismo , Células Fotorreceptoras Retinianas Bastones/metabolismo , Masculino , Femenino
4.
J Immunother Cancer ; 12(4)2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38604810

RESUMEN

BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Melanoma , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Nivolumab/farmacología , Nivolumab/uso terapéutico , Ipilimumab/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología
5.
Curr Opin Oncol ; 36(3): 164-168, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38573205

RESUMEN

PURPOSE OF REVIEW: Patients with biochemically recurrent prostate cancer (BCR) after unsuccessful curative therapies frequently have an indolent and asymptomatic disease course for years. There are no prospective data showing that treating BCR improves overall survival despite new imaging strategies and emerging therapeutic data. Managing BCR requires a unique perspective in oncology that balances toxicities and disease kinetics. RECENT FINDINGS: Prostate specific membrane antigen (PSMA) imaging is now widely available and can define subclinical disease in patients with BCR who otherwise have negative CT and bone scans, but limited data exists showing that treating PSMA-positive disease has long term impact. A phase 3 trial demonstrated that the androgen receptor pathway inhibitor enzalutamide either alone or with androgen deprivation therapy (ADT) was superior in delaying metastasis, relative to ADT alone. Survival benefits from this study remain unknown. SUMMARY: BCR is a heterogeneous population where overtreatment may present greater risk to patients than a disease course that is often indolent. Management of BCR should be individualized based on disease kinetics. Given the unique biology of BCR, future therapeutic research should emphasize an approach that alters disease trajectory without accompanying side effects and should explore options beyond ADT-based strategies.


Asunto(s)
Antagonistas de Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/tratamiento farmacológico , Progresión de la Enfermedad , Antagonistas de Receptores Androgénicos , Tomografía de Emisión de Positrones
6.
Cancer ; 130(9): 1629-1641, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38161319

RESUMEN

BACKGROUND: Patients with localized, unfavorable intermediate-risk and high-risk prostate cancer have an increased risk of relapse after radical prostatectomy (RP). The authors previously reported on part 1 of this phase 2 trial testing neoadjuvant apalutamide, abiraterone, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. The results demonstrated favorable pathologic responses (tumor <5 mm) in 20.3% of patients (n = 24 of 118). Herein, the authors report the results of part 2. METHODS: For part 2, patients were randomized 1:1 to receive either AAPL for 12 months (arm 2A) or observation (arm 2B), stratified by neoadjuvant therapy and pathologic tumor classification. The primary end point was 3-year biochemical progression-free survival. Secondary end points included safety and testosterone recovery (>200 ng/dL). RESULTS: Overall, 82 of 118 patients (69%) enrolled in part 1 were randomized to part 2. A higher proportion of patients who were not randomized to adjuvant therapy had a favorable prostatectomy pathologic response (32.3% in nonrandomized patients compared with 17.1% in randomized patients). In the intent-to-treat analysis, the 3-year biochemical progression-free survival rate was 81% for arm 2A and 72% for arm 2B (hazard ratio, 0.81; 90% confidence interval, 0.43-1.49). Of the randomized patients, 81% had testosterone recovery in the AAPL group compared with 95% in the observation group, with a median time to recovery of <12 months in both arms. CONCLUSIONS: In this study, because 30% of patients declined adjuvant treatment, part B was underpowered to detect differences between arms. Future perioperative studies should be biomarker-directed and include strategies for investigator and patient engagement to ensure compliance with protocol procedures.


Asunto(s)
Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Leuprolida/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/diagnóstico , Antagonistas de Andrógenos/efectos adversos , Andrógenos , Prednisona , Resultado del Tratamiento , Recurrencia Local de Neoplasia/cirugía , Prostatectomía/métodos , Testosterona
7.
J Vasc Interv Radiol ; 35(1): 36-44, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37805172

RESUMEN

PURPOSE: To assess the feasibility and safety of using computed tomography (CT) guidance for ablation of prostate cancer in the salvage setting. MATERIALS AND METHODS: This institutional review board-approved retrospective study of consecutive patients who presented with prostate cancer recurrence and underwent percutaneous CT-guided cryoablation was conducted between July 2020 and September 2022. A total of 18 patients met the inclusion criteria, and a total of 19 procedures were performed. Demographic details; preablation and postablation urinary, rectal, and erectile function assessment; procedure details; and preoperative and postoperative imaging findings and prostate-specific antigen (PSA) values were recorded. RESULTS: The mean treated tumor size was 15.7 mm ± 6.2. Technical success was achieved in 18 of the 19 procedures (94.7%), with 1 procedure aborted due to inability to obtain a safe plane. The mean follow-up time was 10.0 months (range, 2.3-26.7 months) at the time of manuscript preparation. The mean PSA before ablation was 8.1 ng/mL ± 9.3, and postablation PSA nadir was 2.6 ng/mL ± 4.0 (P = .002). Of the 18 patients who had postoperative imaging, 16 (88.9%) had a complete response (ie, no evidence of residual disease), and 2 (11.1%) patients had residual disease. Overall, 16 (88.9%) of the 18 treated patients demonstrated a PSA and/or imaging response to ablation. Mild adverse events occurred in 4 (22%) of the 18 cases. CONCLUSIONS: CT-guided cryoablation appears to be a technically feasible, safe option for treating locally recurrent prostate cancer.


Asunto(s)
Criocirugía , Neoplasias de la Próstata , Masculino , Humanos , Antígeno Prostático Específico , Criocirugía/efectos adversos , Criocirugía/métodos , Estudios Retrospectivos , Estudios de Factibilidad , Resultado del Tratamiento , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/cirugía , Tomografía Computarizada por Rayos X , Recurrencia Local de Neoplasia/cirugía
8.
bioRxiv ; 2023 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-37577497

RESUMEN

Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.

9.
J Immunother Cancer ; 11(3)2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36948504

RESUMEN

BACKGROUND: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. METHODS: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. RESULTS: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death. CONCLUSIONS: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. TRIAL REGISTRATION NUMBER: NCT03117309.


Asunto(s)
Carcinoma de Células Renales , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Ipilimumab/efectos adversos , Terapia Recuperativa
10.
Urology ; 173: 147-148, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36958911
11.
Urol Oncol ; 41(4): 204.e1-204.e6, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36754665

RESUMEN

PURPOSE: Treatment toxicity from surgery radical prostatectomy (RP) or radiation therapy (RT) has been well studied in patients with localized prostate cancer. However, little is known about lingering toxicities in patients who develop metastatic recurrence. We aimed to compare the prevalence of local treatment-related side effects in patients with metastatic recurrence and those in remission, and to explore to what extent medical oncologists address this morbidity. METHODS: This was a single site, cross-sectional study evaluating patient-reported outcomes using the Expanded Prostate Cancer Index Clinical Practice (EPIC-CP) instrument, which measures Health-Related Quality of Life (HRQoL) across urinary, bowel, sexual, and hormonal domains, with higher scores reflecting increased symptom burden. The primary endpoint was differences in overall and domain-specific EPIC-CP scores between the metastatic and localized cohorts, with secondary endpoints evaluating provider interventions for symptom alleviation. RESULTS: Median total EPIC-CP scores were higher in the metastatic cohort (18.0, IQR 13.0-24.0) compared to the localized cohort (10.0, 6.0-15.0) (P < 0.001). This difference was mostly driven by worsening symptoms in the sexual (8.0, 8.0-9.0 vs. 6.0, 3.0-8.0) (P < 0.001) and hormonal domains (2.0, 1.0-6.0 vs. 0.0, 0.0-2.0) (P < 0.001), although there were also differences in the urinary irritation/obstruction (3.0, 0.0-3.0 vs. 1.0, 0.0-2.0) (P < 0.001) and bowel domains (1.0, 0.0-3.0 vs. 0.0, 0.0-0.0) (P < 0.001). There was a trend towards higher scores in patients that had received RT as primary treatment. Medical oncologists rarely changed management in response to local symptoms. CONCLUSION: Prostate cancer patients with metastatic recurrence suffer from a higher burden of localized treatment-related symptoms compared with patients in remission, with primary RT associated with more prevalent toxicity than radical prostatectomy. There is an unmet need for more intensive management of local symptoms. Further studies should focus on factors that portend long term worse morbidity.


Asunto(s)
Neoplasias de la Próstata , Calidad de Vida , Masculino , Humanos , Prevalencia , Estudios Transversales , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Prostatectomía/efectos adversos , Morbilidad
12.
Am J Hosp Palliat Care ; 40(8): 900-906, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36252248

RESUMEN

BACKGROUND: Patients' decision-making and perceptions of outcomes may be impacted by information sources. We investigated use of information by patients and tested the association with patients' perception of treatment outcomes. METHODS: We prospectively surveyed patients with advanced solid cancers and their oncologists regarding benefits/risks of non-curative cancer therapies. We previously reported misperception comparing patients' perceptions of treatment outcomes to those of their oncologist. We report external information use as proportions with binomial confidence intervals (CI) and examined correlations with misperception levels using Spearman's correlation coefficient. RESULTS: Of 125 participants, 70% (95% CI: 61-78) stated that they wanted as much information as possible from their oncologist, and nearly all (95%, 95% CI: 90-98) felt the amount of information provided by their clinician was "just right." Over half (60%, 95% CI: 51-69) wanted at least "a moderate amount" of information from sources outside their oncologist, and 58% (95% CI: 49-67) reported obtaining information from sources outside their oncologist. Over two-thirds (69%, 95% CI: 57-79) of participants felt the information from external sources influenced their decisions "a small amount" or less. There was no correlation between information use and misperception regarding tumor response (r: -.04; P = .60) or treatment toxicity (r: .05; P = .60). CONCLUSION: Many patients sought information from sources outside their oncologist; few felt it substantially influenced treatment choices. External information use was not associated with greater misperception of treatment outcomes. These data suggest sources of information outside the treating oncologists did not substantially influence patient's decision making.


Asunto(s)
Neoplasias , Oncólogos , Humanos , Fuentes de Información , Relaciones Médico-Paciente , Neoplasias/terapia , Neoplasias/patología , Resultado del Tratamiento
13.
Cancer Res ; 83(2): 219-238, 2023 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-36413141

RESUMEN

Abiraterone is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) that slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). Here we report that inhibitors of the mitotic regulator polo-like kinase-1 (Plk1), including the clinically active third-generation Plk1 inhibitor onvansertib, synergizes with abiraterone in vitro and in vivo to kill a subset of cancer cells from a wide variety of tumor types in an androgen-independent manner. Gene-expression analysis identified an AR-independent synergy-specific gene set signature upregulated upon abiraterone treatment that is dominated by pathways related to mitosis and the mitotic spindle. Abiraterone treatment alone caused defects in mitotic spindle orientation, failure of complete chromosome condensation, and improper cell division independently of its effects on AR signaling. These effects, although mild following abiraterone monotherapy, resulted in profound sensitization to the antimitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cancer cell death and entosis. In a murine patient-derived xenograft model of abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC), combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared with either agent alone. Overall, this work establishes a mechanistic basis for the phase II clinical trial (NCT03414034) testing combined onvansertib and abiraterone in mCRPC patients and indicates this combination may have broad utility for cancer treatment. SIGNIFICANCE: Abiraterone treatment induces mitotic defects that sensitize cancer cells to Plk1 inhibition, revealing an AR-independent mechanism for this synergistic combination that is applicable to a variety of cancer types.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Masculino , Humanos , Animales , Ratones , Receptores Androgénicos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Andrógenos , Mitosis
14.
Clin Cancer Res ; 29(1): 50-59, 2023 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-36321991

RESUMEN

PURPOSE: To identify the safety of niraparib, a PARP inhibitor, in combination with Radium-223 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations. PATIENTS AND METHODS: Men with progressive mCPRC following ≥1 line of androgen receptor (AR)-targeted therapy and bone metastases but no documented BRCA-1 or BRCA-2 alterations or bulky visceral disease were included. Niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The highest dose level with a DLT probability <20% was defined as MTD. Secondary endpoints included PSA change and progression-free survival. Exploratory analyses included assessing DNA mutations found in ctDNA as well as gene expression changes assessed in whole blood samples. RESULTS: Thirty patients were treated with niraparib and radium-223: 13 patients received 100 mg, 12 received 200 mg, and 5 patients received 300 mg of niraparib. There were six DLT events: two (13%) for neutropenia, two (13%) for thrombocytopenia, whereas fatigue and nausea each occurred once (3%). Anemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events. For patients with prior chemotherapy exposure, the MTD was 100 mg, whereas the MTD for chemotherapy naïve patients was 200 mg. Whole blood gene expression of PAX5 and CD19 was higher in responders and ARG-1, IL2R, and FLT3 expression was higher in nonresponders. CONCLUSIONS: Combining niraparib with Radium-223 in patients with mCRPC was safe; however, further studies incorporating biomarkers will better elucidate the role of combinations of PARP inhibitors with DNA damaging and other agents.


Asunto(s)
Antineoplásicos , Neutropenia , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Antineoplásicos/uso terapéutico , Radio (Elemento)/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Neutropenia/inducido químicamente
15.
Expert Rev Anticancer Ther ; 22(7): 695-702, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35698870

RESUMEN

INTRODUCTION: Tivozanib is a selective vascular endothelial growth factor receptor (VEGFR)-inhibitor designed to, more specifically, bind to the VEGF receptor with fewer off-target interactions with other tyrosine kinase receptors in the treatment of advanced renal cell carcinoma (RCC). AREAS COVERED: Both preclinical and early clinical studies have suggested tivozanib could be a more potent VEGFR inhibitor with less off-target toxicities for patients. After a complicated clinical development process, the drug was approved by the FDA for third- and fourth-line use in relapsed, refractory renal cell carcinoma (RCC) in March of 2021 based on the results of the TIVO-3 trial. However, questions remain regarding the proper incorporation of tivozanib in the current treatment landscape of RCC. EXPERT OPINION: Here, we review the existing literature surrounding tivozanib and comment on its optimal use in current and future clinical practice. We suggest that tivozanib may be considered in relapsed, refractory RCC in the later-line treatment setting following progression on both immune checkpoint inhibitors (ICIs) and nonselective VEGFR-TKIs. We anticipate the application of tivozanib in RCC will continue to evolve as trials exploring tivozanib in combination with ICIs may move this drug earlier in the future treatment landscape of RCC.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Recurrencia Local de Neoplasia , Compuestos de Fenilurea , Quinolinas , Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Aprobación de Drogas , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular , Estados Unidos , Factor A de Crecimiento Endotelial Vascular
16.
J Clin Oncol ; 40(25): 2913-2923, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35442713

RESUMEN

PURPOSE: To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy. METHODS: Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%. RESULTS: One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively (P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab. CONCLUSION: Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.


Asunto(s)
Carcinoma de Células Renales , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/metabolismo , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Ipilimumab , Nivolumab/efectos adversos
17.
Prostate ; 82(8): 883-893, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35254710

RESUMEN

BACKGROUND: Men of African ancestry (AA) with prostate cancer suffer from worse outcomes. However, a recent analysis of patients treated with the dendritic cell vaccine sipuleucel-T for prostate cancer suggested that AA patients could have improved outcomes relative to whites. METHODS: We conducted a focused literature review of Medline-indexed articles and clinical trials listed on clinicaltrials.gov. RESULTS: We identify several studies pointing to enrichment of inflammatory cellular infiltrates and cytokine signaling among AA patients with prostate cancer. We outline potential genomic and transcriptomic alterations that may contribute to immunogenicity. Last, we investigate differences in host immunity and vaccine responsiveness that may be enhanced in AA patients. CONCLUSIONS: AA patients with prostate cancer may be enriched for an immunogenic phenotype. Dedicated studies are needed to better understand the immune mechanisms that contribute to existing cancer disparities and test immune-based therapies in this population.


Asunto(s)
Negro o Afroamericano , Neoplasias de la Próstata , Negro o Afroamericano/genética , Población Negra/genética , Humanos , Masculino , Neoplasias de la Próstata/terapia , Transcriptoma , Población Blanca
18.
Cancer Res ; 82(8): 1518-1533, 2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-35131873

RESUMEN

Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes ß-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/ß-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/ß-catenin signaling-mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/ß-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/ß-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/ß-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth. SIGNIFICANCE: This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Vía de Señalización Wnt , Comunicación Autocrina , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
19.
Artículo en Inglés | MEDLINE | ID: mdl-34568716

RESUMEN

Metastatic prostate cancer is initially sensitive to androgen receptor inhibition, but eventually becomes castration-resistant prostate cancer (mCRPC). Early use of more intensive therapies targeting androgen receptor and other oncogenic drivers in treatment-naïve primary prostate cancer (PC) may be more effective than that in advanced mCRPC. However, analysis of primary tumors may not reveal targetable metastatic drivers that are subclonal in the primary tumor or acquired at metastatic sites. METHODS: PC samples spanning one patient's clinical course: diagnostic biopsies, pre- or post-enzalutamide metastatic biopsies, and rapid autopsy samples including a patient-derived xenograft (PDX) were analyzed by targeted exome sequencing followed by phylogenetic analysis. RESULTS: Left- and right-lobe primary PC tumors appeared to diverge, with the right acquiring additional shared mutations and striking differences in copy number alterations that later appeared in metastatic samples during the treatment course and at autopsy, whereas the left base tumor maintained a quiet copy number alteration landscape and partitioned into a dead-end node. RB1 loss, a common finding in advanced castration-resistant disease, was identified throughout mCRPC samples, but not in the primary tumor. Significantly, a truncal EGFR-activating mutation (R108K) was identified in the primary tumor and was also found to be maintained in the mCRPC samples and in a PDX model. Furthermore, the PDX model remained sensitive to the EGFR inhibitor erlotinib, despite the presence of both RB1 and BRCA2 losses. CONCLUSION: These findings indicate that truncal alterations identified in primary PC can drive advanced mCRPC, even in the presence of additional strong oncogenic drivers (ie, RB1 and BRCA2 loss), and suggest that earlier detection and targeting of these truncal alterations may be effective at halting disease progression.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Biopsia , Carcinogénesis , Humanos , Masculino , Filogenia , Neoplasias de la Próstata Resistentes a la Castración/genética
20.
Surg Neurol Int ; 12: 237, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34221568

RESUMEN

BACKGROUND: Parkinsonism is a rare complication of non-germinomatous germ cell tumors (NGGCTs) arising from the pineal region. CASE DESCRIPTION: We describe a 23-year-old man who presented with Parinaud syndrome, fatigue, and hypersomnia that were caused by a pineal region NGGCT with yolk sac component and an initial α-fetoprotein (AFP) of 1011.0 ng/ml. MRI revealed that the tumor was causing 10 mm of midline shift and compressing the cerebral aqueduct, the left thalamus, and the midbrain. Obstructive hydrocephalus was relieved by ventriculoperitoneal shunting. Six cycles of induction chemotherapy with ifosfamide, carboplatin, and etoposide reduced tumor size and decreased AFP levels in both serum and cerebrospinal fluid. Following the first cycle, the patient developed asymmetric, bilateral Parkinsonism consisting of bradykinesia, bradyphrenia, facial hypomimia, drooling, and dysphagia. Levodopa, amantadine, and methylphenidate were administered and resulted in symptom improvement. Second look neurosurgery revealed residual yolk sac tumor and a second induction regimen of gemcitabine, paclitaxel, and oxaliplatin was administered for rising AFP. The patient eventually received an autologous bone marrow transplant using a regimen of high-dose carboplatin, thiotepa, and etoposide with concomitant colony-stimulating factor and romiplostim support followed by consolidative proton craniospinal radiotherapy. Posttreatment head MRI showed that no evidence of tumor growth and serum AFP was within normal limits. His Parkinsonism eventually resolved and he was weaned off all dopaminergic drugs. CONCLUSION: Bilateral Parkinsonism from NGGCT in this patient is probably caused by pressure on nigrostriatal tracts, substantia nigra, or both. The Parkinsonian symptoms can be reversed by aggressive treatment of the tumor and administration of dopaminergic drugs.

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