Cancer treatments have continued to improve over the last fifty years with more effective treatments available and survival rates steadily increasing.

High-intensity chemotherapy and radiation treatments have been shown to be generally highly effective, but they can also come with their fair share of physical and emotional burdens on patients and their families. However, new therapies are being developed and are showing promise.

Activating genes

What do doctors turn to when more intense therapies are not an option?

“We frequently offer experimental treatment regimens with commercially available hypomethylating agents (HMAs),” says Dr. Elizabeth Griffiths, a research oncologist and hematologist at Roswell Park Cancer Institute. “These drugs have been shown to offer a survival benefit which is similar to that seen using induction chemotherapy.”

Methylation is an epigenetic mechanism that affects the expression of genes. When DNA is methylated, the gene becomes “silenced” or “turned off.” What HMAs do is demethylate these genes and basically turns them back on,” says Dr. Mohammad Azab, President and Chief Medical Officer of Astex Pharmaceuticals, a member of the Otsuka group. “Usually this can be beneficial with what we call tumor suppressor genes, which in cancer are often methylated.”

Essentially, by demethylating the patients’ DNA, these drugs have the potential to activate cancer-fighting genes and help re-activate cellular pathways associated with normal differentiation and proliferation.

“HMAs will remain the backbone of therapy in the treatment for those ineligible for intensive induction chemotherapy,” says Dr. Michael R. Savona, Director of the Hematology Early Therapeutics Program at Vanderbilt-Ingram Cancer Center, “and they may actually be part of the front-line therapy for select groups of patients.”

“‘The hypothesis is that longer exposure may result in better outcomes for patients with leukemia,’ says Dr. Azab.”

The next generation

The current HMAs are administered or delivered to the patient in high volume given through intravenous or multiple subcutaneous injections. When given this way, they are eliminated very quickly, usually within three hours. This short exposure time limits the ability of the molecule to act on cancer cells.

Dr. Azab and his colleagues at Astex are working on a next-generation hypomethylating agent. “It is one small volume subcutaneous injection that takes less than a minute,” says Dr. Azab.

The new agent is a dinucleotide which is slowly broken in two, unlike current HMAs that are single nucleotides that are deactivated quickly. As such, the new agent can effectively release the active drug in the body for up to 12 hours, potentially giving it the opportunity to affect more cancer cells.

Late-phase testing

“We are currently conducting Phase 3 global clinical trials,” says Dr. Azab, “comparing this investigational drug to existing therapies.” He notes that he and his team are collecting data to prepare for submission for review by the FDA, EU, and Japan. They are also currently conducting trials, which are open for enrollment in patients who have failed prior treatments in acute myeloid leukemia and myelodysplastic syndrome.

“The hypothesis is that longer exposure may result in better outcomes for patients with leukemia," says Dr. Azab.

For practitioners, patients, and loved ones of those suffering with myeloid malignancies, these trials suggest there may be a reason to be hopeful. A new low-intensity therapy could be just around the corner.

“I think this is a very exciting time in the evolution of AML therapies,” adds Dr. Griffiths. “I suspect that HMAs may be the backbone of many of these approaches.”

“In a search for combinations that might provide more options, HMAs are logical partners to other targeted therapies," adds Dr. Jean- Pierre Issa, Co-leader of Cancer Epigenetics at Fox Chase Cancer Center.