Researchers See Promising Results in Non-Cytotoxic Therapy for Myelodysplastic Syndrome

TP53 (p53) is the gene most commonly mutated in cancers. Since p53 is the master regulator of apoptosis, this mutation clashes with the apoptosis-activating (cytotoxic) intent of most cancer treatments. However, a recent Cleveland Clinic study shows that non-cytotoxic concentrations of the DNMT1-inhibitor decitabine will produce p53-independent termination of cancer growth.

“One difference between cancer cells and good stem cells is that cancer cells are frequently able to eliminate their own ‘self-destruct button,’ or p53,” says Cleveland Clinic oncologist Yogen Saunthararajah, MD. “This is a huge problem, since the vast majority of drugs and radiation we currently use to treat cancer are trying to press this self-destruct button.”

Meanwhile, cytotoxic cancer treatments destroy normal stem cells with intact p53 systems. This is particularly problematic in myeloid cancers where blood stem cells, which are already diminished by age and disease, are necessary to reverse the low blood counts that lead to morbidity and death.

Since there are currently no FDA-approved drugs designed to address this significant p53 problem, Cleveland Clinic researchers conducted a study in myelodysplastic syndrome patients to determine if the dose, schedule and route of administration of an existing drug, decitabine, could be redesigned to avoid cytotoxicity and increase effects on the enzyme DNA methyltransferase (DNMT1) instead. The researchers’ hypothesis was that non-cytotoxic depletion of DNMT1 in this way would produce p53-independent termination of cancer growth by restoring expression of proliferation-terminating (MYC-antagonizing) differentiation genes.

Study Methodology

Patients with myelodysplastic syndrome (n = 25) were given small doses of decitabine (0.1-0.2 mg/kg) instead of the FDA-approved dosage of 20-45 mg/m2/day to avoid cytotoxicity (a 75-90 percent reduction). The non-cytotoxic doses were administered 1 to 3 days/week instead of being pulse-cycled for 3 to 5 days over a 4- to 6-week period, to increase probabilities that cancer S-phase entries would coincide with windows of drug exposure needed for S-phase-dependent DNMT1 depletion.

“As expected from the explicit avoidance of cytotoxicity, treatment was very well-tolerated, even by elderly subjects with multiple comorbidities and relapsed disease,” says Dr. Saunthararajah. “Adverse events were related to low neutrophil counts that were present at baseline.”

Study Results

Responses meeting International Working Group criteria for MDS clinical trials occurred in 44 percent of study participants with long-lasting effects. Freedom from transfusion ranged from 186 to 1,152 days, and 20 percent of patients were still transfusion-free after three years on therapy. Non-cytotoxic DNMT1 depletion was confirmed by bone marrow γ-H2AX and DNMT1 measurement, and levels of MYC, the master oncoprotein driver of cell growth and division, significantly decreased.

“The goal of this study was to make low blood counts better,” Dr. Saunthararajah says. “This was achieved to a very meaningful extent in about 40 percent of the patients treated.”

Long-term Implications

“Specialization or differentiation, not self-destruction or apoptosis, is the main natural control on cell growth and division in multicellular creatures such as human beings,” says Dr. Saunthararajah. “Yet we have hundreds of treatments based on killing or apoptosis, and no broad differentiation treatments. This is not because using differentiation is illogical, but because we did not have the science or the drugs to motivate it,” he says.

“This clinical trial indicates that using specialization or differentiation is logical, particularly in cancers that have physically eliminated the apoptosis or self-destruction master switch p53,” he says. “I believe that over the coming decades, and hopefully even over the next years, we will see a broad shift away from using toxic apoptosis and toward using non-cytotoxic differentiation to effectively treat cancer.”

Future Research

The Cleveland Clinic study concluded that decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion to safely and effectively circumvent mutational apoptotic defects. But Dr. Saunthararajah says new and better drug therapies are needed.

“Decitabine, the generic drug we used in this clinical trial, needs to be improved to increase its penetration into solid tissues so that we can use it to treat solid cancers in the same way that we treated blood cancer in this trial,” Dr. Saunthararajah says.

“With support from the National Cancer Institute, the Department of Defense, the Leukemia and Lymphoma Society and kind donors, we are currently conducting additional clinical trials. However, we need many more drugs that work in this non-poisonous differentiation way because cancer will eventually figure out a way to escape the effects of a single drug,” he says.

“Our hope is to convert cancer into a disease that can be controlled as a chronic condition, without bad side effects, using a logical series of differentiation treatments that do not destroy the normal stem cells needed for a long and healthy life. Hopefully, we can eventually get to the point where we have hundreds of differentiation drugs to at least match, if not render obsolete, the hundreds of self-destructive drugs we already have.”

An in-depth description of the methodology and results of the Cleveland Clinic study was published in the Journal of Clinical Investigation.

Photo credit: ©Russell Lee