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Investigators collaborate on developing new drugs designed against the specific mistakes that drive tumors like retinoblastoma.
In the surgical waiting room at St. Jude Children’s Research Hospital, Teresa “Esa” Neiswender is a busy girl. She is working a puzzle with her father, Blair, while trying to reach Minnie Mouse on a blue plastic telephone and keeping an eye on her younger sister Taya, who is still learning to walk.
“Esa finds happiness in every-thing,” says Terise Neiswender, mother of 3-year-old Esa. “She wakes up happy. She likes to sing and cook and color. She makes it possible to take life one day at a time.”
Not bad for a girl who arrived at St. Jude as a 5-month-old with retinoblastoma, a cancer of the retina, the seeing part of the eye. Both of Esa’s eyes were affected. Diagnosed in about 300 U.S. children annually, retinoblastoma is the third most common cancer in infants after leukemia and nerve tumors called neuroblastomas.
The retina provides a connection between the outside world and the brain. In Esa’s case, the tumor in her left eye was so large the retina had detached and pulled away from its normal position at the back of her eye. Chemotherapy and laser treatments helped kill the tumors in both eyes. Injections of an anti-cancer drug in the tissue around the eye also helped destroy cancer cells floating in the jelly-like vitreous within one of her eyes.
The Neiswenders returned to St. Jude early on a recent morning so that Matthew Wilson, MD, could check for any signs Esa’s cancer had returned. Wilson specializes in treating tumors involving the eye and related structures.
Esa is among the 40 percent of retinoblastoma patients who are candidates for a lifetime of close monitoring. The same genetic mistake responsible for her retinoblastoma leaves her at greater risk for developing other cancers. This checkup brought good news: Wilson found no new tumors.
The news has also been good recently in the St. Jude laboratories where scientists such as Michael Dyer, PhD, are working to understand both normal retinal development and the missteps that lead to the uncontrolled cell growth that is a hallmark of all cancers, including retinoblastoma. Dyer, of Developmental Neurobiology, is among the St. Jude investigators leading a push to develop new drugs designed against the specific mistakes driving tumors like retinoblastoma. Researchers expect this new generation of medicines to be more effective and less toxic.
Earlier this year a project led by Dyer and R. Kiplin Guy, PhD, Chemical Biology and Therapeutics chair, identified a molecule with the potential to be the founding member of a new class of cancer drugs. The drugs would be the first designed specifically against a childhood tumor.
Known as SJ-172550, the new compound targets what researchers believe is the Achilles heel of retinoblastoma and certain other cancers. Earlier work from Dyer’s lab found the vulnerability. Scientists showed the vast majority of retinoblastoma tumors, as well as nearly 20 percent of breast, colon and lung cancers, have extra copies of the gene that carries instructions for assembling a protein named MDMX.
That is a problem because an overabundance of MDMX disrupts the pathway used to eliminate rogue or damaged cells. A protein named p53 plays a critical role in that pathway, inducing the death of the damaged cells that give rise to cancer. But when MDMX levels are high, p53 gravitates toward MDMX, slipping into the same pocket where SJ-172550 also fits. With p53 out of the picture, cell division proceeds unchecked with disastrous results.
The new insight led investigators to screen a chemical library of nearly 300,000 compounds effective against the excess MDMX. After identifying SJ-172550 as a possible candidate, researchers demonstrated in the laboratory that the molecule killed retinoblastoma cells that carried extra copies of the MDMXgene. Even more tumor cells died when investigators combined SJ-172550 with another experimental drug targeting a different protein that at excessive levels disrupts the p53 pathway.
Scientists are now tweaking SJ-172550 to enhance its medicinal qualities, including making it smaller and more easily dissolved in liquids.
“It is like taking a puzzle piece and figuring out ways to make it fit even better,” Dyer says. “That is a lot of work. It will take years, which is why drug development takes so long.”
Dyer says the continuing effort to find and develop compounds like SJ-172550 illustrates the strength of St. Jude drug development efforts. Those include Chemical Biology and Therapeutics, where faculty and staff focus on finding and then enhancing potential new drugs. In Pharmaceutical Sciences, researchers focus on how candidate drugs move through the body, including how they are absorbed, broken down and eventually eliminated. Finally, St. Jude investigators have developed a variety of laboratory models where promising new drugs can be tested.
“This project highlights why at St. Jude it works so well. We have all three of the research components combined with outstanding clinical care. That is what makes St. Jude special,” Dyer says.
Patients like Esa are already benefiting. She enrolled in a research study, or protocol, that included the drugs topotecan and vincristine given intravenously combined with carboplatin injections around her right eye. St Jude researchers pioneered the use of topotecan for retinoblastoma. “We believe the protocol saved her eyes,” her mom says.
Dyer, Guy and other St. Jude investigators are pursuing additional promising leads and collaborations to find new, more tailored treatments of retinoblastoma and other childhood tumors. The prospects include the experimental drug nutlin-3a. The compound is in early testing in adult cancer patients, and St. Jude researchers reported evidence it might play a role against retinoblastoma—possibly in combination with the newly identified SJ-172550.
With current treatments, more than 95 percent of St. Jude retinoblastoma patients are cured. But Wilson says treatment remains arduous for patients and families. Surgical removal of one or both eyes is sometimes necessary.
“The overall trend in cancer therapy has been toward more targeted, less toxic therapies. But childhood tumors are rare. They are not the kind of cancers being targeted by drug companies,” Wilson says. “I am enthusiastic about the collaboration underway at St. Jude. We are identifying candidate drugs and moving those candidate drugs forward. We are making progress in understanding childhood cancers like retinoblastoma and ways to treat it.”
Reprinted from Promise Summer 2010