Noncytotoxic Differentiation Treatment

By Yogen Saunthararajah, MD

Today, only five types of nonresectable cancers are routinely cured: certain lymphomas and myeloid leukemias, and testicular cancer. Although there has been exciting progress, most recently with immune-checkpoint inhibitors, most patients with disseminated cancer still face a difficult and uncertain future, with financial distress adding to the burdens of the diagnosis.

This situation prompts several important questions:
• Why can we cure some disseminated cancers but not others?
• Why are treatments so arduous?
• Why does oncology drug development have a 95 percent failure rate, with consequent high costs that are shifted to patients?

The answers ultimately lie in biology. Thus, it is worth reflecting on results of recent large-scale cancer genomic studies.

Confronting a Paradox

First, the single most commonly inactivated gene in all cancer types is that for p53, the master transcription factor regulator of apoptosis. This is very significant, since radiation and hundreds of drugs, including agents in development, intend apoptosis (cytotoxicity). That p53-system alterations subvert cytotoxic oncotherapeutic intent has been shown by several in vitro studies, but perhaps it is most vividly illustrated by the near absence of TP53 mutations in the few disseminated cancers that are routinely cured (e.g., testicular cancer). Conversely, refractory/relapsed testicular cancer, and incurable subsets of the few other usually curable disseminated malignancies, are characterized by TP53 mutation/deletion and/or homozygous CDKN2A (p16) loss. And of course the cancers that are most notoriously difficult to treat are characterized by the highest rates of p53 loss.

A second revelation has been essentially universal inactivating events in coactivator genes (e.g., PBRM1, ARID1A) ‒ that is, deletion of cofactors needed by master transcription factors to activate target genes. These findings explain a striking paradox of cancer cells, including cancer stem cells: Cancer stem cells express high levels of the master transcription factors that usually drive terminal differentiation, yet the target genes of these transcription factors are epigenetically repressed rather than being activated.

Coactivator disruption causes unbalanced recruitment of corepressor counterparts (e.g., DNA methyltransferase 1 [DNMT1]) to the transcription factors, repressing instead of activating proliferation-terminating differentiation target genes. Importantly, inhibiting these specific corepressors (e.g., DNMT1) renews differentiation and restores physiologic, p53/p16-independent cell cycle exits. Wonderfully, the same treatments increase self-renewal of normal stem cells, which express high levels of master stem cell transcription factors, not differentiation-driving transcription factors.

Dealing with Decitabine Inactivation

The deoxycytidine analog decitabine depletes DNMT1 and potentially can translate this science into a therapeutic strategy. (Decitabine and 5-azacytidine are the only FDA-approved drugs that can be repositioned for noncytotoxic corepressor inhibition). With NIH support, we demonstrated that repositioning decitabine to avoid cytotoxicity and increase DNMT1 depletion was remarkably safe and effective in treating myelodysplastic syndromes, including in elderly subjects with multiple comorbidities.

Historically, however, use of decitabine to deplete DNMT1 in solid tissue cancers has been unsuccessful in the clinic, most likely because of the enzyme cytidine deaminase (CDA), which rapidly inactivates decitabine, severely curtailing solid tissue distribution and oral bioavailability and drastically abbreviating in vivo half-life to ~10 minutes compared with ~12 hours in vitro.

To address this severe pharmacokinetic problem, we have combined decitabine with an inhibitor of CDA ‒ tetrahydrouridine (THU) ‒ and proved in mice, baboons and humans (phase 1 clinical trial) that the combination produces ~tenfold improvement in oral bioavailability, as well as the low Cmax and multihour Tmax needed for noncytotoxic DNMT1-depletion by decitabine in multiple tissues.

Building on the previous clinical trial, the National Cancer Institute’s Myeloproliferative Disorders (MPD) Research Consortium will conduct a multicenter trial of oral THU-decitabine in transfusion-dependent MPDs. This has been an academic drug development effort at Cleveland Clinic, but we have managed to raise the funds to also initiate clinical trials of this approach to treat p53-mutated/deleted solid tumor malignancies, and will begin clinical trials in 2015. We hope to demonstrate that oral THU-decitabine administration can actualize DNMT1’s potential as a clinically relevant molecular target, with a distinctive p53/p16 pathway of action that can meaningfully salvage (without toxicity) refractory/resistant metastatic solid tumors and liquid malignancies.

A Way Forward

Differentiation, not apoptosis, is the main physiologic control on cell growth and division in metazoa. Yet in contrast to hundreds of treatments whose intent is cytotoxicity ‒ an essentially futile goal in the face of p53/p16-inactivation ‒ there are only two oncotherapeutics used in the clinic with explicit noncytotoxic differentiation intent: all-trans retinoic acid (ATRA) and arsenic. Unfortunately, for mechanistic reasons, ATRA and arsenic activity is restricted to the rare myeloid cancer acute promyelocytic leukemia.

Science indicates that noncytotoxic differentiation treatment via inhibition of specific corepressors can be broadly effective, sparing normal stem cells and circumventing mutational apoptosis defects in cancer cells. We hope that addressing these most common genetic alterations in cancer in this rational way will decrease drug failures in phase 2 and 3 trials, thereby reducing the overall cost of cancer drug development that currently is shifted to patients and the public. We plan to determine whether oral THU-decitabine can be the first of many agents to translate this science and begin to correct an irrational imbalance in the oncotherapeutic portfolio.

Dr. Saunthararajah is a staff member of Cleveland Clinic’s Department of Hematology and Medical Oncology and a Professor of Medicine at Cleveland Clinic Lerner College of Medicine. He can be reached at saunthy@ccf.org or 216.444.8170.

Photo Credit ©Russell Lee