By Vamsi Velcheti, MD, and Yogen Saunthararajah, MD
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Lung cancer is the leading cause of cancer-related death in the United States. Despite decades of biological progress, clinical gains have been only modest, and lung cancer has proved essentially resistant to multiple oncotherapeutics.
One reason for broad-spectrum resistance is that oncotherapeutic diversity is more apparent than real in a key regard: Most agents are common in intending apoptosis (cytotoxicity) as the final pathway of action.
This is a problem because the master transcription factor regulator of apoptosis is p53, and TP53 is the single most frequently inactivated gene in lung cancer, fundamentally subverting p53-mediated apoptosis as a therapeutic intent.
Excitingly, however, a breakthrough occurred in 2015 with the Food and Drug Administration’s approval of immune checkpoint inhibitors as second-line treatment for lung cancer. Wide-ranging genetic and proteomic aberrations in lung cancer present to the immune system as “non-self,” triggering an immune response. Immune checkpoint inhibitors basically curtail the ability of a tumor to counter or suppress this pre-existing immune reaction. In other words, these drugs are active only in tumors that appear to be “immune-primed” — that is, enriched in lymphocytic infiltrates requiring that the tumor use immune checkpoints to survive.
Unfortunately, only a minority of lung cancers are immune-primed; most tumors epigenetically silence the expression of neo-antigens or non-self proteins needed for immune-priming. For example, cancer-specific (embryonic) antigens, which have been observed to trigger immune responses, are often epigenetically silenced in lung cancer.
A key mediator of such epigenetic silencing is the epigenetic protein DNA methyl-transferase 1 (DNMT1). Moreover, DNMT1 mediates the epigenetic repression of hundreds of late-differentiation genes in cancer cells — genes that would otherwise antagonize MYC function and terminate cell growth and division independent of p53, as they do during normal lung tissue ontogeny.
Thus, DNMT1 has been validated as a molecular target whose inhibition not only increases neo-antigen/ non-self protein expression by lung cancer cells but also triggers direct termination of cancer growth by p53-independent mechanisms. The same treatment preserves normal stem cells and immune effectors, since these are not using aberrant epigenetics to avoid terminal differentiation.
Decitabine is a DNMT1-depleting drug that the FDA has approved as a treatment for myeloid cancer. Unfortunately, decitabine as currently formulated is not suitable for translating the above science into effective clinical lung cancer treatment, because decitabine is rapidly destroyed in solid tissues by the enzyme cytidine deaminase (CDA). As such, decitabine distribution into solid tissues is trivial. Attempts to compensate by increasing the dose or using continuous infusion elevates decitabine in sensitive tissues (e.g., bone marrow) to toxic levels, while target solid tissues still receive inadequate exposure.
To overcome this basic pharmacologic limitation of decitabine, we have combined it with tetrahydrouridine (THU), an inhibitor of CDA, and demonstrated in a phase 1 clinical trial that its half-life is transformed from a few minutes to many hours, with excellent decitabine oral bioavailability and with the low Cmax and extended Tmax through solid tissues needed for viable, non-cytotoxic epigenetic treatment of solid tumor malignancies.
This non-cytotoxic epigenetic-therapeutic profile:
In other words, oral THU-decitabine could be an ideal platform by which to augment the activity of recently approved immune checkpoint inhibitors such as nivolumab. Accordingly, with support from the American Society of Oncology and the Scott Hamilton CARES Initiative, a proof-of-concept trial of oral THU-decitabine, optimized for non-cytotoxic DNMT1-depletion, together with nivolumab, will be enrolling soon at Cleveland Clinic.
Dr. Velcheti is a staff member of Cleveland Clinic’s Department of Hematology and Medical Oncology and an Assistant Professor of Medicine at Cleveland Clinic Lerner College of Medicine. He can be reached at velchev@ccf.org or 216.444.8665.
Dr. Saunthararajah is a staff member of the Department of Hematology and Medical Oncology and Co-Leader of Cleveland Clinic Cancer Center’s Developmental Therapeutics Program. He is also 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
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