Tubacin for Myeloma Therapy
Summary Background: Nearly 10 million people throughout the world are diagnosed with cancer each year. The direct and indirect medical costs to treat cancer total more than $180 billion each year, and in the United States alone, cancer takes the lives of 1,500 people on average each day. One key target of recent cancer therapy approaches involves HDAC inhibitors, with over 15 different clinical trials currently ongoing. The exponential growth in the level of research activity surrounding the histone deacetylases (HDACs) witnessed over the past decade has been driven by the ability of HDAC inhibitors to modulate transcriptional activity. In tissue culture studies, this therapeutic class is able to block angiogenesis, cell cycling, and promote apoptosis and differentiation. HDAC inhibitors function by binding to the enzymes' active sites and inhibiting the site-specific deacetylation of lysine residues on target substrates.A major drawback with the use of HDAC inhibitors in clinical trials is their toxicity. HDAC inhibitors target specific classes of HDACs (HDACs consist of three classes and a total of at least eighteen isoforms) rather than individual members, which is believed to contribute to side effects. A case in point is Curagen's lead HDAC inhibitor PXD101 for the treatment of multiple myeloma and T-cell lymphoma. In a phase I clinical trial the most common side-effects reported were fatigue, nausea, and vomiting as well as acute decrease in renal function. In another example, a phase II clinical trial of Gloucester Pharmaceuticals HDAC inhibitor depsipeptide for treatment of metastatic neuroendocrine tumors revealed severe cardiotoxicity. The promise of more effective treatments with HDAC inhibitors lies in the discovery of agents that can target isoform specific HDAC's. This would lead to reduced toxicity and greater efficacy in the treatment of cancer.
Applications Novel Technology: Tubacin and its optimized, novel analogs are a set of first-in-class HDAC inhibitors that target a specific HDAC isoform, HDAC6. HDAC6 inhibition by tubacin and analogs has far reaching implications for the treatment of both solid and hematological tumors. HDAC6 deacetylation of microtubules has been shown to be instrumental in a cell migration. In solid tumors that demonstrate the capacity to metastasize, alpha-tublin monomers exhibit a hypoacetylated state. Cell-based assays with human lung A549 cells demonstrate that addition of tubacin increases alpha-tubulin acetylation (at125 nM) and reverse HDAC6-mediated cell motility. The specificity of tubacin for HDAC6 was also revealed: tubacin exhibited a 3-fold selectivity for HDAC6 over HDAC1 and HDAC4.
Researchers have also shown that HDAC6 inhibition by tubacin is a lead-treatment for the treatment of protein degradation disorders. Cancer cells are highly dependent on protein degradation due to continuous cell cycling, hypermutation, and chromosomal rearrangements. The proteasome and the aggresome are the two principal cellular structures involved in intracellular protein degradation. The primary role of the proteasome is the targeted degradation of ubiquitinated proteins, while the aggresome is a juxtanuclear complex of misfolded proteins, chaperones, and proteasome components. In vitro studies reveal that HDAC6 inhibition by tubacin prevents aggresome formation.
Joint studies conducted at Harvard and Dana Farber Cancer Institute have shown that a combination therapy of the proteasome inhibitor Velcade® with tubacin induces p53 independent apoptosis effects in a mouse model of multiple myeloma. Therefore, the inhibition of both pathways; that is, the proteasome by Velcade®, and the aggresome by tubacin, may lead to more effective treatments for cancer. The following lists other key results from the study:
-Tubacin significantly enhances Velcade-induced cytotoxicity in multiple myeloma cell lines. MM.1S (A) and RPMI8226 (B) cells were cultured with Velcade (5 and 10 nM) in the presence (5 and 10 uM) or absence of tubacin for 24h. Cytotoxicity was assessed by MTT assay. Figure 1 below demonstrates that tubacin significantly (p< 0.01) augmented cytotoxicity triggered by Velcade in both cell lines. Importantly, the combination treatment of Velcade with tubacin does not trigger cytotoxicity in normal peripheral blood mononuclear cells. -Caspase and PARP cleavage is induced by the combination of Velcade with tubacin. -Both compounds demonstrated marked results in Velcade® resistant cell lines -Tubacin (5 ?M) alone does not alter cell cycle profile, whereas bortezomib (5 nM) alone triggers increased G2/M phase in multiple myeloma cell lines. The combination of tubacin and bortezomib triggers significantly increased sub-G0/G1 phase cells, suggesting that combination treatment triggers apoptotic cell death. Advantages: Tubacin is the first ever domain-selective HDAC inhibitor, targeting one of the two catalytic domains of HDAC6. At low micromolar concentrations, tubacin causes tubulin hyperacetylation and marked antiproliferative, proapoptotic effects against myeloma cell lines. In addition, tubacin potently sensitizes myeloma cells to subtoxic concentrations of bortezomib. Importantly, no adverse effect of tubacin on peripheral blood mononuclear cells was noted, with or without bortezomib. Recent medicinal chemistry efforts have led to a number of analogs with activity profiles in the low nanomolar range.
Testing of tubacin revealed that its effect on tubulin acetylation and other cellular processes does not correlate with gene expression. The non-specific HDAC inhibitor TSA altered expression of 232 genes above a 1.3-fold threshold value. In contrast, in the presence of tubacin no genes showed a significant alteration in expression using the same statistical criteria. Tubacin also does not affect cell cycle arrest, mitotic spindle formation, chromosome orientation and cell differentiation. The increase of ?-tubulin-acetylation levels by tubacin prohibits cell motility without affecting total levels of tubulin and cell morphology.
Commercial Applications: Tubacin and its related HDAC6 specific inhibitors are to be used in the clinic as cancer therapies. In addition to multiple myeloma, other types of cancers where HDAC6 inhibition by tubacin may be efficacious include leukemia, lymphoma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, and liver cancer.
Currently a number of studies are currently underway looking into various other indications in which HDAC6 may play a role. Tubulin acetylation is widespread in the nervous system suggesting an important role of this modification in brain function. In agreement, Alzheimer's disease reduced alpha-tubulin-acetylation levels have been observed, suggesting that tubacin could potentially be used to treat neurodegenerative disorders by increasing balpha tubulin acetylation. In other examples, the protein deposition disorder is Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, familial amytrophic lateral sclerosis, amyloidosis, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's disease, or Lewy body dementia.
Market: The market for agents to treat cancer and neurodegenerative disorders, such as Alzheimer's disease is large. There are over 21 million people living in the United States with cancer, with over 1 million newly diagnosed individuals each year. For multiple myeloma, there are over 43, 000 people living in the U.S. with the disease and 14,600 new cases diagnosed each year. In 2004, U.S. sales of VELCADE were approximately $143.1 million. Nearly 4 million Americans live with Alzheimer's disease, while 1 million individuals live with Parkinson's disease. In the case of Alzheimer's disease, there is still no drug that targets the pathway the leads to b-amyloid plaques. With significant ongoing research into the role of HDAC6 in various diseases it is anticipated that several new indications will arise over the coming years.
Publications: PNAS, April 15, 2003, Vol. 100, No. 8, pp. 4389-4394 PNAS, June 14, 2005, Vol. 102, No. 24, pp 8567-8572 For Further Information Please Contact the Director of Business Development Laura Brass Email: [email protected] Telephone: (617) 495-3067
Inventor(s): Schreiber, Stuart L.
Type of Offer: Licensing
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