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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Webhead who wrote (15990)	2/27/1998 12:03:00 PM
From: Henry Niman	Respond to of 32384

Ed, The News & World Report is very related to LGND. Dr Warrell does the LGND retinoid clinical trials at Sloan Kettering. Moreover, Ligand exclusive consultant Ron Evans published on the deacylases last year and again last week (last week's results were virtually identical to the report that you uploaded).

To: Webhead who wrote (15990)	2/27/1998 12:13:00 PM
From: Henry Niman	Respond to of 32384

The abstract of the Nature paper published last week has already been uploaded: Message 3471645

To: Webhead who wrote (15990)	2/27/1998 12:18:00 PM
From: Henry Niman	Respond to of 32384

Here's the initial clinical data (in HUMANS) on Targretin from Warrell's lab at Memorial Sloan Kettering: J Clin Oncol 1997 Feb;15(2):790-795 Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. Miller VA, Benedetti FM, Rigas JR, Verret AL, Pfister DG, Straus D, Kris MG, Crisp M, Heyman R, Loewen GR, Truglia JA, Warrell RP Jr Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, NY 10021, USA. millerv@mskcc.org PURPOSE: The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer. PATIENTS AND METHODS: Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29. RESULTS: Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism. CONCLUSION: LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials. Publication Types: Clinical trial PMID: 9053506, UI: 97178773

To: Webhead who wrote (15990)	2/27/1998 12:28:00 PM
From: Flagrante Delictu	Read Replies (1) \| Respond to of 32384

Webhead, >> of MICE... & MEN << Thanks for the birthday wishes & even greater thanks for pointing out this most significant article. Talk about science coming our way! Wow. Bernie

To: Webhead who wrote (15990)	2/27/1998 12:43:00 PM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

Ed, The two types of transcription factors (zinc-fingers and leucine zippers) is very exciting as is the involvement of the histone deacylases. LGND's paper also showed synergy between rexinoids and inhibitors of the deacylases. The applications are far broader than APL and non-Hodgkins Lymphomas (which did wonders for IDPH's stock price). Recent papers have also implicated retinoblastomas and I'm sure that the list will grow much larger. Evan's published one of five papers in the same issue of Cell last May, and in the past few weeks there has been another burst of publications in leading publications like Nature, Science, and Cell.

To: Webhead who wrote (15990)	2/27/1998 3:15:00 PM
From: Henry Niman	Respond to of 32384

Here's the abstract from Nature Genetics: Volume 18 Number 2 - February 1998 articles Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL Li-Zhen He1, Fabien Guidez2, Carla Tribioli1, Daniela Peruzzi1, Martin Ruthardt3, Arthur Zelent2 & Pier Paolo Pandolfi1 1Department of Human Genetics, Memorial Sloan-Kettering Cancer Center and Molecular Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA. 2Leukaemia Research Fund Center at the Institute for Cancer Research, Chester Beatty Laboratories, 2307 Fulham Road, London SW3 6JB, UK. 3Istituto Oncologico Europeo, Milano, Italy and Department of Haematology, Med. Klinik III, J.W. Goethe-University, 7 Theodor Stern Kai, 60590 Frankfurt/Main, Germany. Correspondence should be addressed to P.P.P. e-mail: p-pandolfi@ski.mskcc.org Acute promyelocytic leukaemia (APL), associated with chromosomal translocations involving the retinoic acid receptor alpha gene (RARA) and the PML gene, is sensitive to retinoic acid (RA) treatment, while APL patients harbouring translocations between RARA and the PLZF gene do not respond to RA. We have generated PML-RARA and PLZF-RARA transgenic mice and show here that these fusion proteins play a critical role in leukaemogenesis and in determining responses to RA in APL, because PLZF-RARA transgenic mice develop RA-resistant leukaemia, while PML-RARA mice are responsive to RA treatment. We demonstrate that both PML-RARalpha and PLZF-RARalpha fusion proteins can act as transcriptional repressors and are able to interact with nuclear receptor transcriptional co-repressors, such as SMRT. PLZF-RARalpha , but not PML-RARalpha , can form, via its PLZF moiety, co-repressor complexes which are insensitive to RA. Histone deacetylase inhibitors such as Trichostatin A (TSA), in combination with RA, can overcome the transcriptional repressor activity of PML-RARalpha and PLZF-RARalpha as well as the unresponsiveness of PLZF-RARalpha -expressing leukaemic cells to RA. Thus, our findings unravel a crucial role for transcriptional silencing in APL pathogenesis and resistance to RA in APL.