January 15, 2018 (Vol. 38, No. 2)

Ashley Jean Yeager Freelance Writer GEN

Scientists May Be Better Able to Destroy Tumors and Possibly Reverse CNS Decline

If the genome represents the book of life, and the coding elements are highlighted, bookmarked, or underlined passages that represent a genotype—then perhaps DNA methylation and histone modification are the footnotes that give extra context to the genotype, pointing to what should be read or skipped.

Information derived from these annotations, taken together with the clearly defined genotype, inform what we see in a phenotype.

Such epigenetic marks are essential for cells to develop normally. When these marks are attributed improperly, healthy cells can transform into diseased ones.

“Global changes in the epigenetic landscape are a hallmark of cancer,” Shikhar Sharma, Ph.D., principal scientist and project leader at Pfizer, and colleagues wrote in a 2010 Carcinogenesis article.1

Some of those changes include epigenetic marks that may be added to or removed from histones though the action of enzymes such as histone demethylases (HDMs) and histone deacetylases (HDACs). Researchers have begun to home in on these proteins, looking for drugs that inhibit their actions in the cell.

At the 15th annual Discovery on Target conference held in Boston, MA in September 2017, scientists described developments in designing epigenetic cancer drugs. The talks highlighted a promising trend—epigenetic modification could be the next wave in cancer therapy, especially when exploited in tandem with the administration of other medications, 4SC AG’s Chief Development Officer Frank Hermann, M.D., told GEN.

Inhibiting an Epigenetic Eraser

Epigenetic inhibition could be a viable approach for patients with the blood cancer acute myeloid leukemia (AML). A hallmark of the disease is the proliferation of cells that have not completely matured. These cells, which typically turn into white blood cells to fend off infection, don’t differentiate. Instead, they stay in a stem cell−like state.

Research has shown that lysine-specific histone demethylase 1 (LSD1) plays an essential role in the self-renewal of these “leukemic stem cells,” Incyte principal investigator Sang Hyun Lee, Ph.D., tells GEN. Building on this finding, Dr. Lee and colleagues developed an LSD1 inhibitor called INCB059872, which spurs myeloid cell differentiation. That helps to eradicate the cells that are at the root of the leukemia, something conventional therapies can’t do, Dr. Lee says. Preclinical studies also suggest INCB059872 could help combat small-cell lung cancer and Ewing Sarcoma, and clinical trials are currently underway to test the drug’s efficacy in patients with sickle-cell disease, as well as its safety in patients with advanced malignancies.

What could be truly exciting, Dr. Lee notes, is the combination of LSD1 inhibitors with antibodies that block programmed cell death-1 (PD-1), a cell surface receptor that keeps the immune system in check. Together, the one-two punch could spur the body’s own immune system to attack cancer cells.

Modifying Other Epigenetic Markers

Aside from HDMs such as LSD1, HDACs have become cancer targets. At 4SC AG, researchers are working on 4SC-202, an inhibitor of HDAC1, HDAC2, and HDAC3. Preclinical tests show that the inhibitor can change the microenvironment of a tumor by increasing populations of antitumor immune cells in the area. 4SC-202 also appears to increase the expression of tumor-associated antigens and immunomodulatory molecules in cancer cell lines. Specifically, CD8+ cells, also known as cytotoxic T cells, burst onto the scene, while other immune system suppressor cells drop off, Dr. Hermann tells GEN.

Like the developers of LSD1 combination therapies, 4SC AG researchers are pairing an epigenetic drug, in this case an HDAC inhibitor, with immunotherapies. Inactivating immune system checkpoints such as PD-1 and treating cells with 4SC-202 can inhibit tumor growth.2 A clinical trial to test the efficacy of combining the epigenetic cancer drug with pembrolizumab, a humanized antibody that inhibits PD-1, is currently underway. Together, the drugs appear to prevent cancer cells from evading detection.

“I think the future of oncology, in terms of treating solid tumors, will be these combination therapies,” Dr. Hermann says.

Homing In on HDAC6

But the focus is not entirely on HDACs that act on histones. HDAC6, for example, can deacetylase tubulins, proteins that join together to form microtubules. This threadlike material is a staple of the cell cytoplasm and helps transport genetic material to cell nuclei during mitosis. Microtubules help cancer cells move, which is why tubulins are targets for current cancer drugs such as Taxol (paclitaxel).

Because HDAC6 is associated with tubulin, it has become a prime target in cancer therapy. Studies show HDAC6 is overexpressed in solid tumors.3 It plays a role in the movement and survival of tumor cells.

Researchers are looking for ways to inhibit HDAC6, preventing it from deacetylasing tubulins. One inhibitor being developed is Karus Therapeutics’ KA2507. In preclinical studies, this inhibitor reduced the expression of PD-1, causing tumor suppressor genes to switch on.4 Tumor cell division was inhibited, and apoptosis began in unhealthy cells overexpressing HDAC6.

Another HDAC6 inhibitor Karus is working on is KA2237, which inhibits primary tumor growth and metastasis. Karus’ COO and CSO Stephen Shuttleworth, Ph.D., reported in 2016 that the inhibitors could work in combination with one another to treat cancer.4 The co-therapy tactic could potentially become important clinically, and could be used to overcome resistance mechanisms in both solid and hematological cancers. Both aforementioned investigational candidates from Karus are being tested in clinical trials.

Moving beyond Cancer

Alan Kozikowski, Ph.D., founder and CEO of StarWise Therapeutics, is also working on HDAC6 inhibitors. He and colleagues have developed several candidates, some of which are being tested by pharmaceutical companies such as Celgene. One of the candidates is ACY-1215 (Ricolinostat). It is, in combination with other drugs, currently in clinical trials for the treatment of multiple myeloma. There’s also Tubastatin A, which, in a recent study, seemed to force glioblastoma cells toward self-destruction.5 In another experiment, the drug candidate showed promise in treating Alzheimer’s disease.6

But Dr. Kozikowski seems most excited about StarWise-100, a new drug candidate that could be a therapeutic option to treat Charcot-Marie-Tooth disease, an inherited nerve disorder characterized by the loss of muscle use in the legs and loss of sensation to touch. The disorder causes patients to trip, sprain their ankles, and feel the tingling known as “pins and needles.”

Pointing to preclinical test results (which are still unpublished at time of print), Dr. Kozikowski asserts that animals with the disease that were treated with StarWise-100 regained sensory abilities and movement. StarWise is now trying to “fast track” the drug for studies to treat other conditions, such as Rhett syndrome.

Why might an HDAC6 inhibitor work for these diseases? Because of mitochondria, Dr. Kozikowski suggests. Acetylation of tubulin creates threads that facilitate the movement of mitochondria, specifically in hippocampal neurons. If tubulin is deacetylated, however, mitochondria don’t move so smoothly, interrupting nerve cell activity and, ultimately, muscle movement. With that in mind, Dr. Kozikowski is collaborating with a group of researchers to develop novel HDAC6 inhibitors to treat glioblastoma, Alzheimer’s disease, and other central nervous system diseases.

But, Dr. Kozikowski says, there’s something really important to keep in mind when designing HDAC inhibitors: the drugs are capable of damaging genetic information and, as a result, could be a source for secondary cancers.

“You don’t want to cause a patient to develop tumors while trying to cure [his or her] neurodegenerative disease,” Dr. Kozikowski emphasizes. “What we need to do is make drugs safer and better.” 

References

1. S. Sharma et al., “Epigenetics in Cancer,” Carcinogenesis 31(1), 27–36 (January 1, 2010), https://doi.org/10.1093/carcin/bgp220.
2. F. Hermann, “Clinical Development of 4SC-202, A Combined Epigenetic Inhibitor of HDAC Class I and LSD1, to Overcome Anti-PD-1 Refractoriness and Increase Efficacy of Checkpoint Inhibition,” J. Clin. Oncol. 35(15_suppl), doi: 10.1200/JCO.2017.35.15_suppl.e14096.
3. G.I. Aldana-Masangkay and K.M. Sakamoto, “The Role of HDAC6 in Cancer,” J. Biomed. Biotechnol. (published online November 7, 2010), doi:10.1155/2011/875824.
4. S.J. Shuttleworth, “Abstract 3996: KA2237 and KA2507: Novel, Oral Cancer Immunotherapeutics Targeting PI3K-p110?/p110? and HDAC6 with Single-Agent and Combination Activity,” Proceedings: AACR 107th Annual Meeting 2016, (April 16–20, 2016, New Orleans, LA, published July 2016), doi:10.1158/1538-7445.AM2016-3996.
5. Z. Wang et al., “HDAC6 Promotes Cell Proliferation and Confers Resistance to Temozolomide in Glioblastoma,” Cancer Lett. 379(1), 134–142 (August 28, 2016).
6. L. Zhang et al., “Tubastatin A/ACY-1215 Improves Cognition in Alzheimer’s Disease Transgenic Mice,” J. Alz. Dis. 41(4), 1193–1205 (2014).

 

 

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