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RXR
RXR
RXR(3)
RXR is a type of nuclear receptor that is activated by 9-cis retinoic acid.(1) There are three RXRs: RXR-α, RXR-β, and RXR-γ, encoded by the RXRA, RXRB, RXRG genes, respectively. RXR heterodimerizes with subfamily 1 nuclear receptors: CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR. As with other type II nuclear receptors, the RXR heterodimer in the absence of ligand is bound to hormone response elements complexed with co-repressor protein. Binding of agonist ligands to RXR results in dissociation of co-repressor and recruitment of co-AP, which, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein.(2)

Drugs/Indications
Marketed Drugs
Generic Code Old Code Brand Company Indication trials
alitretinoin Panretin Mkt: Kaposi trials
bexarotene Targretin Valeant Mkt: CTCL; P3: NSCLC; P2: BC, Kaposi, AML, MDS, NHL; P1: solid, thyroid trials
retinoic acid noncorporate Mkt: acute promyelocytic leukemia; P3: AML, NSCLC; P2: neuroblastoma, SCLC, leukemia, MDS, neroendocrine, melanoma, NSCLC; P1: BC, solid, lymphoma trials
tretinoin Vesanoid, ATRA, Renova, Atralin, Refissa, Tretin-X, Avita, Retin-A Molecular Insight Mkt: acute promyelocytic leukemia; P3: AML, basal, squamous, NSCLC, MM, brain, RCC, AML, neuroblastoma; P2: melanoma, PC, lymphoma; P1/2: MDS, MM trials
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
fenretinide noncorporate P3: bladder, cervical, BC, Ewing's; P2: ovarian, peritoneal, PC, lung, HNN, RCC, brain, CNS, GBM, neuroblastoma, melanoma; P1/2: HL; P1: solid, MDS, leukemia, MM, AML, ALL, NHL trials
isotretinoin Accutane Roche P3: neuroblastoma, RCC, HNN; P2: MM, cervical, esophageal, lung, PC trials
acitretin Soriatane P2: skin, melanoma trials
rexinoid NRX-4204 NRX 194204, AGN-194204 NuRx P2: NSCLC, PC; P1: various (terminated) trials
tamibarotene INNO-507 TM-411,TOS-80T,Am-80 CytRx P2: acute promyelocytic leukemia, NSCLC trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
peretinoin NIK-333 Failed to meet endpoing; P3: HCC trials
retinol AMT2003 Auron development terminated; P2/3: CRC, GIST, PC; P2: HCC trials
NRX 195183 NuRx withdrawn: P2: acute promyelocytic leukemia trials
TAC-101 terminated; P2: HCC trials
News
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References

1. Allenby G, Bocquel M-T, Saunders M, Kazmer S, Speck J, Rosenberger M, et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proceedings of the National Academy of Sciences. 1993;90(1):30-4.

2. Retinoid_X_receptor. [cited]; Available from: http://en.wikipedia.org/wiki/Retinoid_X_receptor.

3. Yardy G, Brewster S. Wnt signalling and prostate cancer. Prostate cancer and prostatic diseases. 2005;8(2):119-26.



News
Friday, September 16, 2016 3:40 AM| Basu P, Jenson AB, Majhi T, Choudhury P, Mandal R, Banerjee D, Biswas J, Pan J, Rai SN, Ghim SJ, Miller D|IARC Scientific Papers|Labels: RXR, cervical cancer, clinical trial

Phase 2 Randomized Controlled Trial of Radiation Therapy Plus Concurrent Interferon-Alpha and Retinoic Acid Versus Cisplatin for Stage III Cervical Carcinoma.

Int J Radiat Oncol Biol Phys. 2016 Jan 1;94(1):102-10

Authors: Basu P, Jenson AB, Majhi T, Choudhury P, Mandal R, Banerjee D, Biswas J, Pan J, Rai SN, Ghim SJ, Miller D

Abstract
PURPOSE: Because a combination of retinoic acid, interferon-alpha, and radiation therapy demonstrated synergistic action and effectiveness to treat advanced cervical cancers in earlier studies, we designed this randomized phase 2 open-label trial to assess efficacy and safety of interferon alpha-2b (IFN) and 13-cis-retinoic acid (RA) administered concomitantly with radiation therapy (IFN-RA-radiation) to treat stage III cervical cancer.
METHODS AND MATERIALS: Stage III cervical cancer patients were randomized to study and control groups in a 1:1 ratio. All patients were treated with radiation therapy; study arm patients received IFN (3 × 10(6) IU subcutaneously) 3 times a week for 4 weeks and daily RA (40 mg orally) for 30 days starting on day 1 of radiation, whereas control arm patients received weekly cisplatinum (40 mg/m(2)) for 5 weeks during radiation. Patients were followed for 3 years. The primary endpoint was overall survival at 3 years.
RESULTS: Patients in the study (n=104) and control (n=105) groups were comparable for clinicopathological characteristics, radiation therapy-related variables and treatment response. Proportions of disease-free patients in the study and control groups were 38.5% and 44.8%, respectively, after median follow-up of 29.2 months. Hazard ratios were 0.67 (95% confidence interval [CI]: 0.44-1.01) and 0.69 (95% CI: 0.44-1.06) for overall and disease-fee survival, respectively, comparing the study group to control, and demonstrated an inferior outcome with RA-IFN-radiation, although differences were statistically nonsignificant. Kaplan-Meier curves of disease-free and overall survival probabilities also showed inferior survival in the study group compared to those in the control. Acute toxicities of chemoradiation were significantly higher with 2 acute toxicity-related deaths.
CONCLUSIONS: Treatment with RA-IFN-radiation did not demonstrate survival advantage over chemoradiation despite being less toxic. The trends predicted an inferior outcome with the RA-IFN combination.

PMID: 26700705 [PubMed - indexed for MEDLINE]

Wednesday, September 14, 2016 4:23 PM|A. Slominski|JournalTOCs API - Journal of Investigative Dermatology (875 articles)|Labels: HIF, RXR, melanoma

476 Expression of retinoic acid receptor-related orphan receptors (ROR) α and γ correlates with hypoxia in cutaneous melanomas
A.A. Brozyna W. Jozwicki, M. Pawlikowska, E. Wedrowska, A. Slominski
Journal of Investigative Dermatology, Vol. 136, No. 9 (2016) pp. S241 -
Hypoxia is one of the hallmarks of the tumor microenvironment and up-regulation of hypoxia-inducible factor 1 alpha (HIF-1α) is considered as a negative prognostic marker. Recently the role of retinoic acid–related orphan receptor (ROR) α and γ in hypoxia signaling pathway have been identified. RORα and RORγ are involved in many physiological functions in several organs. Previously we showed that RORs are expressed in human normal skin and melanocytic tumors including nevi and melanomas. Furthermore, we reported that HIF-1α expression and HIF-1α dependent pathways can be regulated by melanogenesis and are related to poorer prognosis of melanoma.

Monday, June 6, 2016 4:58 AM|HAO, X., XIAO, H., JU, J., HEWITT, S. M., MORSE, H. C.|Anticancer Research recent issues|Labels: RXR, CRC

Background/Aim: The family of retinoid X receptors (RXRs) including RXRα, β and , is involved in regulating cell proliferation, differentiation, apoptosis and development. Materials and Methods: In order to characterize the role of RXRs during colorectal carcinogenesis, the expression of RXRs in human and azoxymethane (AOM)-induced rat colorectal tumors was profiled by immunohistochemistry. Results: Both human and rat normal colorectal epithelia and hyperplasia exhibited strong nuclear, but weak cytoplasmic staining for all three proteins. Expression of RXRα, β and was significantly reduced in rat carcinomas compared to high-grade dysplasia whether in aberrant crypt foci or in adenomas. All three proteins displayed dramatically reduced nuclear expression in both human adenomas and carcinomas. Reduced expression of RXRα and RXR seems more significant than RXRβ in both human and rat carcinomas. Conclusion: Reduced expression of RXRs is associated with colorectal carcinogenesis in both humans and AOM-treated rats.

Friday, March 11, 2016 12:00 AM|Labels: RXR, liver cancer

A research group lead by a Special Unit Leader, Soichi Kojima, of RIKEN Center for Life Science Technologies, reported a molecular basis for nuclear-cytoplasmic transport of transglutaminase 2 and a role of acyclic retinoid in it.