Three Targeted Agents in Development for Molecular Subtypes of Leukemia

Three novel therapeutic agents for the treatment of hematologic malignancies are under development at Cleveland Clinic Cancer Center.

“Our current focus in the area of myeloid neoplasia is on development of targeted agents for molecular subtypes of leukemia defined by specific mutations and improvement of HSC in various diseases,” says Jaroslaw Maciejewski, MD, PhD, Chair of the Department of Translational Hematology and Oncology Research.

Together with his collaborators James Phillips, PhD, Babal Kant Jha, PhD, Valeria Visconte, PhD, and Yogen Saunthararajah, MD, Dr. Maciejewski directs Cleveland Clinic’s cancer drug discovery efforts. The portfolio of drugs is growing, and multiple patents have been filed.

“As practicing hematologists, we see an urgent need to have better drugs available. Our clinical practice and patients provide a constant inspiration for the drug discovery efforts,” says Dr. Maciejewski. Below is a brief overview of three drugs currently under development.

Targeting TET2 mutations in myeloid neoplasia

One study yielded a development of a novel class of TET-specific inhibitors for TET2 mutant-associated diseases. TET2 encodes a methylcytosine Fe2+-dependent DNA-dioxygenase that catalyzes the conversion of 5-methylcytosine-DNA (5mC) to 5-hydroxymethylcytosine-DNA (5hmC) and is involved in active DNA methylation. Loss-of-function TET2 mutations are the most common mutations found in myeloid neoplasia and some lymphomas.

“TET2 mutations are good targets for drug discovery because they are common, occur early in the disease process and affect fundamental processes of leukemogenesis; we learned a lot about the consequences of these mutations through study of the disease,” explains Dr. Maciejewski. “Our goal was to develop a TET-specific inhibitor capable of inducing synthetic lethality in diseases with TET2 mutations.”

Using a structure-guided, targeted discovery approach, Dr. Maciejewski and his collaborators designed and synthesized a novel class of TET-specific inhibitors, which demonstrated dose-dependent inhibition of dioxygenase activity, as well as promising results in vitro and in preclinical murine disease models. An agent from this class, designated as TETi76, was shown to selectively induce cell death in TET2 mutation cells with minimal toxicity to residual healthy bystander cells.

Another unexpected biological activity of this agent included its positive effects on healthy stem cells, which point to potential application of this class of drugs in bone marrow failure syndromes. TET DNA dioxygenase inhibitors are a completely new class of drugs not previously used in oncology.

Inhibiting FABP5-mediated retinoic acid signaling in AML

In a separate study, cancer center investigators reported on a novel therapeutic strategy for acute myeloid leukemia (AML) based on highly specific fatty-acid-binding protein 5 (FABP5) inhibitor.

“ATRA [all-trans retinoic acid] has been a miracle drug for acute promyelocytic leukemia [APL], but other more common forms of AML have been resistant,” explains Dr. Maciejewski.

Similar to the cellular retinoid-binding protein II (CRABP-II), FABP5 serves as a retinoic acid (RA) transporter. In leukemia cells with high levels of CRABP-II and low levels of FABP5 (e.g., APL), RA activates the retinoic acid receptor (RAR) which leads to cell growth arrest and apoptosis. However, in leukemia cells with high FABP5 expression, RA activates the peroxisome proliferator-activated receptor b/d (PPAR b/d) instead of RAR, which leads to cell (tumor) growth and proliferation. Thus, inhibiting FABP5 constitutes a potential novel therapeutic approach for types of AML previously resistant to ATRA.

“There is great need for improvement of outcomes of these AML patients, and the combination of FABP5 with ATRA may constitute a novel mutation-agnostic therapy approach,” he says.

Improving the function of HSCs in aging and bone marrow failure

Nicotinamide adenine dinucleotide (NAD+) related to vitamin B3 is an essential cofactor implicated in the regulation of cellular processes, oxidative stress and bone marrow function. NAD+ levels decline with age, and preventing this process has been shown to prolong the life span. Research suggests that some of these effects may be attributed to the effects of NAD+ on stem cells including hematopoietic stem cells (HSCs).

“The levels of NAD+ in bone marrow are regulated by CD38, an NAD+ degrading enzyme,” says Dr. Maciejewski. “We have identified an agent that selectively inhibits enzymatic activity of CD38. This agent has been further modified to improve its biologic activity in terms of optimization of HSC function.”

This is a unique property because, to date, only a few agents have been shown to prevent relentless HSC attrition in vitro.

“We have observed that CD38 inhibitor allows for the preservation of stem cell pool in vitro even if the proliferation and inherent differentiation have been induced by hematopoietic growth factors,” he says. “Of importance is that the positive effects of the lead compound ccf1172 on normal HSCs were not associated with proleukemogenic properties. Leukemic cells were not stimulated by this drug — indeed, they were inhibited. Our results point to a promising novel therapeutic strategy expansion of HSCs involving CD38 in vivo in inherited or acquired bone marrow failure states and ex vivo in generating better bone marrow grafts for transplantation.”