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Targeted Chemotherapy for Treatment-Resistant Tumor Cells

The key challenge in treatment of cancer is prevention of tumor recurrence. Most cancer-related deaths are due to this resurgence of metastatic tumors. Invariably, this secondary pool of invasive cells develops resistance against most therapeutic interventions. How cancers evade primary treatments and the mechanisms that contribute to drug resistance has been a subject of intense investigation. In some cases, tumor cells avoid chemotherapy by evading the immune system and exiting the cell cycle in a process termed “cancer dormancy.”

Ramin Shiekhattar, Ph.D.
Ramin Shiekhattar, Ph.D.

To combat this, a collaborative study between laboratories of Ramin Shiekhattar, Ph.D., and Sylvester Director Stephen D. Nimer, M.D., and the Jean-Christophe Marine Laboratory of Molecular Cancer Biology at KULeuven in Belgium has developed a new anti-cancer approach called “targeted chemotherapy,” which encourages tumor cells to commit suicide but does not trigger dormancy. The study was published in the journal Genes & Development.

 “One of the major strategies cancer cells use to avoid chemotherapy is to basically stop growing,” said Dr. Shiekhattar, co-leader of the Cancer Epigenetics Research Program and senior author on the study. “That’s cancer’s strategy. Our response is to fool tumor cells into thinking they have DNA damage, while simultaneously preventing them from going into dormancy. This proved quite promising against melanoma with mutations in BRAF or NRAS, a type of melanoma for which there are no available effective treatments currently.”

Targeted chemotherapy is, in some ways, a contrarian approach to treating cancer. Most targeted therapies inhibit kinases, enzymes that turn proteins on. However, Dr. Shiekhattar’s team is doing the opposite, inhibiting a phosphatase, an enzyme that turns proteins off.

This particular phosphatase, called PP2A, performs at least two important tasks. First, it helps modulate the DNA damage response. Chemotherapy destroys cancer by breaking DNA during cell division, triggering the damage response and ultimately (hopefully) cell death.

PP2A turns off the enzymes responsible for sending that cell death message, allowing diseased cells to survive. However, inhibiting PP2A keeps those proteins on – indefinitely – telling cancer cells they’ve sustained severe DNA damage, when in fact none has actually occurred.

PP2A also contributes to cell dormancy. Dormant cells divide much less often, giving cancer an escape hatch to avoid treatment. By preventing dormancy, PP2A inhibition makes cancer more vulnerable.

Once the team had identified PP2A as a potential therapeutic target, they found a small molecule compound, called phendione, to turn the enzyme off. They found the compound was quite effective at eliminating otherwise treatment-resistant human tumors in animal models.

“Inhibiting PP2A with phendione produced the double advantage of transmitting the DNA damage response, without actually damaging the DNA, and telling the cell cycle to keep going and prevent dormancy,” said Dr. Shiekhattar. “These are the two tenets of an effective anti-cancer drug.”

While it’s unlikely phendione will progress into human clinical trials, it is likely that a phendione-like molecule will usher in a new era of phosphatase-based therapy. This study is proof-of-concept that PP2A inhibition could be used to treat resistant melanoma, encouraging the research community to identify other inhibitors and phosphatases as targets for cancer therapy.

“Because it modulates both the DNA damage response and cancer cell dormancy, PP2A represents a very promising target,” said Dr. Shiekhattar. “We are continuing to study this pathway and its role in cancer.”