Targretin oral (bexarotene oral)

We found that in non-malignant mammary epithelial cells the combination of the chemopreventive agents bexarotene (Bex) and carvedilol (Carv) suppresses the zymogen granule protein 16B (ZG16B, PAUF) through an interaction of ARID1A with a proximal enhancer. In contrast, Bex + Carv inhibited colony formation, reduced Ki67 levels, ZG16B expression and glucose uptake in MDA-MB231 xenografts. These data establish ZG16B as a druggable pro-tumorigenic target in breast cell transformation and suggest a key role of the matrisome network in rexinoid-dependent antitumor activity.

No abstract available

Additionally, the median half maximal inhibitory concentration (IC50) of bexarotene, cyclopamine, etoposide, and paclitaxel in LYPD3 high group was significantly lower than that in LYPD3 low group. LYPD3 is involved in many BPs of LC, such as regulating immune cell infiltration and affecting prognosis. Therefore, LYPD3 may have potential value as a biomarker for prognosis and immunotherapy in LC.

PEG IFN α-2a for MF/SS showed ORR of 53%, TTNT of 9.2 months, superiority of combination regimens in comparison to monotherapy and doses of 180 mcg/weekly related to higher ORR.

P1, N=20, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

Our data support predictive validity of prognostic factors and models in MF and identified further potential parameters associated with poor survival. Prospective studies on prognostic indices across disease stages and treatment modalities are needed to predict and improve survival.

Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.

The serum levels of MMP-2 and MMP-9 was significantly increased in bexarotene non-responded patients compared to responded patients. Our present study suggested the significance of MMP-9 and PAI-1 for the progression of MF stage toward to the tumor stage, and could be a therapeutic target in future.

ICRTGs may be reliable biomarkers for the molecular typing of patients with OVC, enabling the prediction of prognosis and immunotherapy efficacy.

This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.

These real-world outcomes are consistent with ALCANZA results, demonstrating favorable outcomes with BV vs. OST in patients with CTCL previously treated with ≥1 systemic therapy.

P1, N=12, Recruiting, National Cancer Centre, Singapore | Trial completion date: Jun 2023 --> Sep 2025 | Trial primary completion date: Jun 2023 --> Sep 2024

The drug sensitivity analysis showed the high-expression subgroup may be more susceptible to Bexarotene, Doxorubicin, Gemcitabine and Tipifarnib. It may be related to the immunosuppressive microenvironment and could be an underlying HCC treatment strategy. However, the conclusions still require further validation studies.

The phase 3 ALCANZA trial showed significantly improved objective responses lasting ≥4 months and progression-free survival with the CD30-directed antibody–#drug conjugate brentuximab vedotin (BV) vs physician’s choice of methotrexate or bexarotene in CD30- expressing CTCL (Horwitz, et al. The 24-week interim results of this prospective real-world evidence study assessing the effectiveness of BV treatment in patients with CD30-expressing CTCL demonstrated favorable clinical outcomes and a tolerable safety profile of BV.

Background Bexarotene and 9cUAB30 are oral retinoid X receptor (RXR) agonists which inhibit proliferation in breast cancer. There was no evidence by IHC of antigen expression loss with sequential RXR agonist with the vaccine. Conclusions The RXR agonists have an immunostimulatory role with plasmid cancer vaccines, but further modification of the immune environment may be needed for prevention vaccines.

For other neurological diseases, its mechanisms of action include inhibiting inflammatory responses, up-regulating microglial phagocytosis, and reducing misfolded protein aggregation, all of which aid in alleviating neurological damage. Here, we briefly discuss the characteristics, applications, and adverse effects of bexarotene, summarize its pharmacological mechanisms and therapeutic results in various neurological diseases, and elaborate on the problems encountered in preclinical research, with the aim of providing help for the further application of bexarotene in central nervous system diseases.

Necroptosis genes are implicated in the pathogenesis and progression of breast cancer and are thought to impact the prognosis and response to drug treatments in individuals with BRCA. Consequently, understanding the role of these genes in breast cancer may aid in identifying more precise and efficacious therapeutic targets.

Treatment strategies and associated responses included: topical steroids (10/12 patients; 4/10 responded), short-course prednisone (5/12 patients; 4/5 responded), oral methotrexate (3/12 patients; 1/3 responded), oral bexarotene (4/12 patients; 2/4 responded), phototherapy (1/12 patients; 1/1 responded), oral cyclophosphamide (1/12 patients; 1/1 responded), JAK2 inhibitor (1/12 patients; 1/1 responded). The frequency and persistence of MAR in clinical practice appears greater than previously described. Given the high efficacy and response durability to mogam, understanding precipitating factors and effective treatments for MAR is critical to better application of mogam for patients with CTCL.

Treatment with radiotherapy and later bexarotene was established; despite which the disease progressed with new tumor lesions in the thorax and extremities...He was referred to Hematology and they decided to start systemic treatment with brentuximab, cyclophosphamide, doxorubicin, prednisone and subsequent consolidation with autotransplantation if complete remission was achieved. We present this case due to the infrequent extracutaneous involvement: tumor stages increase the probability of systemic dissemination, although esophageal involvement is exceptional. Follow-up adapted to the tumor stage is required for early detection of metastases.

At this point, treatment with mogamulizumab was considered, but the patient’s condition deteriorated rapidly, and he died one month later. Treatment options for SS are very limited and associated with low responses. Brentuximab was approved in Europe, in December 2021, to the treatment of CD30+ CTLC, after at least one previous systemic treatment. In clinical trials, it has shown to be more effective than bexarotene and methotrexate, with longer progression-free survival time, but with no improvement in overall survival.

We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide's anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.

Based on cuproptosis-related lncRNAs, we constructed and validated a novel risk signature that may be used to predict immunotherapy efficacy and prognosis in LUAD patients.

Intravenous injection of transcription factor E3 shRNA or intraperitoneal injection of compound C, an AMP-activated protein kinase blocker, inhibited the effects of bexarotene. These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways, promotes autophagy, decreases reactive oxygen species level, inhibits pyroptosis, and improves motor function after spinal cord injury.

In human ACCs, myoepithelial-like cells act as progenitors of ductal-like cells, and myoepithelial-to-ductal differentiation is promoted by RAR/RXR signaling. Suppression of RAR/RXR signaling is lethal to ductal-like cells and represents a new therapeutic approach against human ACCs.

While 11 patients received acitretin as second line treatment after methotrexate and/or phototherapy. The treatment of MF in stages IA/IB/IIA is based on topical treatments and phototherapy. It is only in case of failure of this first line of treatment or in more advanced stages (≥ IIB) that systemic treatments are used, including retinoids. In clinical practice, acitretin is most frequently used in cases of extensive lesions, relapsing after topical treatments and phototherapy and in case of contraindication to other immunomodulators.

The present findings suggest that BMI ≥25 kg/m is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

In addition, the immunoreactive cells were calculated using digital microscopy, suggesting that the ratio of CD25+ cells among TILs was significantly increased in patients who responded to bexarotene (p = 0.0209), whereas there were no significant differences in the ratios of CD8+ cells, granulysin+ cells, and Foxp3+ cells among TILs between responder and non-responder patients. Collectively, the ratio of CD25 expression among TILs might be a predictive biomarker for the efficacy of bexarotene.

Both simvastatin and atorvastatin could upregulate KLF2 expression levels, depress cell viability, and confer increased sensitivity to bexarotene in CTCL cells. These results provide new insights into the pathogenic mechanisms of KLF2 underlying CTCL progression. Stains, clinically lipid-lowering drugs, may play a novel role in CTCL therapy via inducing KLF2 overexpression

Brentuximab vedotin compared with MTX or BEX was cost-effective for CD30-expressing MF and pcALCL. Brentuximab vedotin's higher drug costs versus MTX or BEX were offset by decreased post-progression and end-stage management costs, and showed a 0.25 QALY gain versus MTX or BEX, and increased the proportion of patients eligible for potentially curative SCT.

Median number of previous treatment was 3 (range 1-4); all of them but one had bexarotene, 7 had steroids, 4 interferon alpha, 3 monochemotherapy with Gemcitabine and 2 polichemotherapy (CHOP/CHOEP), 3 Psoralene Ultra-Violet A (PUVA), 1 radiotherapy and 2 photopheresis. In our experience Mogamulizumab alone or in combination show good response and disease control in R/R patients with MF and SS. The treatment was well tolerated and no safety concern was noticed. Cutaneous T-cell lymphoma, Mycosis fungoides

Existing therapies such as the RXR retinoid bexarotene and the anti-CCR4 monoclonal antibody mogamulizumab may act through the CTCL TME by impacting the CCL22:CCR4 axis, while cancer-associated fibroblasts (CAFs) in the CTCL TME contribute to drug resistance, as well as a Th2 milieu and tumor growth via secretion of pro-tumorigenic cytokines. Recent molecular advancements have contributed to our understanding of the pathogenesis of CTCL and shed light into the potential mechanisms of existing therapies. Further understanding of the CTCL TME may fuel the discovery of novel therapies for CTCL.

RXR agonists have been developed as therapeutic agents for cutaneous invasive T-cell lymphoma (e.g., bexarotene (1)) and investigated as potential anti-inflammatory agents...Here we show that the fluorescent RXR agonist CU-6PMN (3), designed by our group, can be useful for assessing RXR binding to PPARγ/RXRα, and that the binding data differ from those of RXRα alone. This screening method opens a new avenue for binding assays for RXR heterodimers.

MSU-42011 targets immune regulatory and biosynthetic pathways, while bexarotene acts on several proteoglycan and matrix metalloproteinase pathways. Exploration of these differential effects on gene transcription may lead to an increased understanding of the complex biology behind RXR agonists and how the activities of this diverse class of compounds can be utilized to treat cancer.

No abstract available

Furthermore, Bexarotene, Bleomycin, Gemcitabine, etc., were identified as potential therapeutic compounds for HNSCC. This novel cuproptosis-related lncRNAs prognostic signature could predict prognosis and help propose novel individual therapeutic targets for HNSCC.

The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.

The IC ranged from 1.1 to 11 µM, with vemurafenib, dabigatran etexilate and everolimus being the strongest inhibitors. Moreover, a mechanistic static model suggested that vemurafenib, bexarotene, dabigatran etexilate, rifapentine, aprepitant, and ivacaftor could almost fully inhibit intestinal BCRP, increasing the exposure of concomitantly administered rosuvastatin over 90%. Therefore, clinical studies are warranted to investigate whether these drugs cause BCRP-mediated DDIs in humans.

We then assessed the sensitivity to other TKIs nilotinib and dasatinib in the RXRA OE cells and found increased sensitivity...Next we assessed the effect of clinically available ligands specific to RXRA (Acitretin,Bexarotene and 9-cis-Retinoic acid) on CML CD34+ cells in combination with IM...Interestingly RXRA OE reduced the engraftment potential of CML cells in-vivo, indicating a mechanism for altering the stemness capacity of CML cells. Further work is ongoing to elucidate the molecular mechanisms orchestrated by RXRA in CML cells.

In ALCANZA (Horwitz 2021), patients with CD30-positive pcALCL or MF randomized to brentuximab vedotin (BV) vs physician's choice of methotrexate or bexarotene had a significantly higher objective response rate (ORR) lasting ≥4 months (ORR4; 54.7% vs 12.5%; P<0.001) and longer median progression-free survival (PFS; 16.7 vs 3.5 months; P<0.001) and time to next treatment (TTNT; 14.2 vs 5.6 months; P<0.001) at a median follow-up of 45.9 months...In the OST cohort, the most common 2L therapies were methotrexate (11.6%), mogamulizumab (9.1%), and bendamustine (9.1%) monotherapies... Real-world outcomes with BV in patients with CTCL who received ≥1 prior systemic therapy were consistent with results from ALCANZA, demonstrating favorable clinical outcomes with BV.

CP466722, Pyrimethamine, AKT inhibitor VIII, Embelin, Cisplatin, QS11, Bexarotene, and Midostaurin negatively correlated with PTP4A3 associated with the three datasets. The results indicate that PTP4A3/PRL-3 is an important prognostic factor for LIHC and is a new potential prognostic detection target. The discovery of the 8 drugs that were negatively associated with PTP4A3 provided a new direction that can be developed in the future for the treatment of LIHC.