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Chromatin as a Cancer Target – Part II: Chromatin Erasers

September 9, 2014

By Garrett Rhyasen, PhD


This week’s blog will be a continuation of the three part series on Chromatin as a cancer target. If you missed last week’s post on Chromatin Writers, you can get up to speed here. Today we’ll be moving onto Chromatin Erasers. Like Chromatin Writers, Erasers possess an intrinsic enzymatic activity. The interplay between these two enzyme classes contributes to the dynamic nature of chromatin.

Chromatin Erasers

Erasers catalyze the removal of chemical modifications onto chromatin. The diversity of this enzyme class is represented by histone deacetylases (HDACs), phosphatases, demethylases and deubiquitinases. Eraser-catalyzed removal of histone marks can result in rapid changes in local chromatin structure, allowing for the expression – or repression of – sets of genes. In some cases, genes under the regulation of Chromatin Erasers are important for normal developmental processes, and aberrant misregulation can result in the development of cancer. Thus, in theory Chromatin Erasers are logical cancer drug targets.

This landmark study by Kadoch et al, published in Nature Genetics, identified frequent mutations in chromatin remodeling complexes across human cancer.
This landmark study by Kadoch et al., published in Nature Genetics, identified frequent mutations in chromatin remodeling complexes across human cancer.

The cancer epigenetics field has become far more interesting with the application of next-generation sequencing technologies. For example, recently published meta-analyses of cancer genome sequencing data have revealed that nearly 20% of all human cancers harbor mutations in the SWI/SNF chromatin-remodeling complex (1, 2). This is a staggering figure, and not far behind the frequency of p53 mutations (~50%) across human cancers. However, we’ve known about p53 mutations in cancer for over two decades (3). Much energy has been spent on developing chemical methods to reactivate the p53 pathway, but unfortunately we are still without a bona fide p53 pathway drug (4). This, in part, could be due to the challenges faced when attempting to drug loss-of-function cancer mutations. Unlike the p53 field, the cancer epigenetics is relatively nascent. There are many emerging examples of cancer-dependent epigenetic functions. The chromatin effectors in question offer accessible molecular surfaces, featuring greasy, hydrophobic pockets. Thus, many epigenetic targets are readily drugable from a medicinal chemistry standpoint.

Considering the topic of today’s discussion many of you might be reminded of HDAC inhibitors. For more on HDACs I’ll refer you to an excellent review here. I won’t be covering HDACs today; instead I want to delve into a relatively new body of translational research, which implicates histone demethylases as cancer targets.


Until 2004, histone methylation was thought to be an irreversible modification. This prevailing view was eventually disrupted with the discovery of histone demethylases. The first demethylase characterized was the lysine-specific histone demethylase 1 (LSD1) (5). Just to be clear, LSD1 is unrelated to its psychotropic synonym lysergic acid diethylamide. At any rate, this initial finding was followed by the discovery of an entire family of histone demethylases, namely the jumonji (JmjC)-domain-containing lysine demethylase family (6, 7). So, after all, histone methylation is dynamic, and reversible.

So, why should you care? Well, not only is LSD1 a regulator of chromatin structure, it’s overexpressed in several cancer types, and in these cancers LSD1 depletion results in suppressed cancer cell growth (8, 9). To date, the most compelling indication for LSD1 inhibition appears to be Leukemia. For example, LSD1 has been shown to sustain the oncogenic potential of Mixed Lineage Leukemia (MLL) in vivo (10). Another study providing intrigue was aimed at providing an epigenetic explanation for why Acute Myeloid Leukemia (AML), unlike Acute Promyelocytic Leukemia (APL), does not respond to all-trans retinoic acid (ATRA). It turns out that in AML, LSD1 overexpression is correlated alterations in histone methylation of ATRA-responsive genes. When LSD1 inhibition is applied to these AML cells it primes them to differentiate in the presence of ATRA (11).

As an interesting corollary, epigenetic priming seems to be a potential strategy to enhance the activity of many anti-cancer agents, especially immunomodulatory drugs. This approach is currently being prosecuted by investigator-sponsored trials using azacytidine as a priming agent (see trial information here, here, and here).

LSD1 Inhibitors – Competitive Landscape

The list of companies publicly working on LSD1 as a cancer target is quite short (Table 1). It’s important to note that LSD1 is ubiquitously expressed in humans – this could potentially lead to a nasty toxicity profile, and might explain why more companies have not yet stepped into the fold. Although LSD1 is overexpressed in cancer, there have not yet been reports demonstrating gain-of-function mutations, which may otherwise have expedited excitement over LSD1 drug discovery. Even though it’s early days, big pharma hasn’t let LSD1 go unnoticed. For example, GlaxoSmithKline has developed their own LSD1 inhibitor and initiated two phase I trials – one in Small Cell Lung Cancer and another in AML. Additionally, earlier this year Roche struck a deal with Oryzon, a private European-based biotech company, over the development and potential commercialization of Oryzon’s lead asset, ORY-1001, an LSD1 inhibitor (see the release here). ORY-1001 is currently being tested in an AML patient population in Spain (see here for EU Clinical Trial Register).

Table 1. Competitive Landscape for Cancer-focused LSD1 Inhibitors

Company Drug Name Target Development Stage Trial Number Indication Formulation
Oryzon; Roche ORY-1001 LSD1 Phase I 2013-002447-29 Acute Myeloid Leukemia Oral
GlaxoSmithKline GSK2879552 LSD1 Phase I NCT02177812NCT02034123 Small Cell Lung Cancer, Acute Myeloid Leukemia Oral

Finally, there’s been a significant amount of recent intellectual property filed (See here for a list complied by Nature Reviews Drug Discovery) surrounding LSD1 and other histone demethylases in the cancer space. Many of the patents were filed from academic institutions; I wouldn’t be surprised to see a NewCo form in the coming months on the basis of recent IP. At any rate I’ll be watching safety signals closely as the GSK and Oryzon drugs progress through their phase I studies.

Stay tuned for the third, and final installment of this series: ‘Chromatin as a cancer target – Part III: Chromatin Readers.’


  1. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, and Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nature genetics. 2013;45(6):592-601.
  2. Shain AH, and Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PloS one. 2013;8(1):e55119.
  3. Hollstein M, Sidransky D, Vogelstein B, and Harris CC. p53 mutations in human cancers. Science (New York, NY). 1991;253(5015):49-53.
  4. Khoo KH, Verma CS, and Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nature reviews Drug discovery. 2014;13(3):217-36.
  5. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, and Shi Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941-53.
  6. Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P, and Zhang Y. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006;439(7078):811-6.
  7. Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006;125(3):467-81.
  8. Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, Field HI, Neal DE, Yamaue H, Ponder BA, et al. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. International journal of cancer Journal international du cancer. 2011;128(3):574-86.
  9. Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R, Ora I, Pajtler K, Klein-Hitpass L, Kuhfittig-Kulle S, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer research. 2009;69(5):2065-71.
  10. Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke BF, Jordan AM, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer cell. 2012;21(4):473-87.
  11. Schenk T, Chen WC, Gollner S, Howell L, Jin L, Hebestreit K, Klein HU, Popescu AC, Burnett A, Mills K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nature medicine. 2012;18(4):605-11.

Disclaimer: All opinions expressed on Oncology Discovery are my own and do not necessarily represent the position of my employer. The information presented within this article is not a solicitation for investment.

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