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Chemist Fights a Very Personal War on Cancer

Chemist Fights a Very Personal War on Cancer

Chemist Jonathan Sessler, a cancer survivor, joins with a colleague from MD Anderson to develop a better drug for ovarian cancer.

sessler 2006 mattlankes-webChemist Jonathan Sessler, a cancer survivor, is working with a colleague at the MD Anderson Center to develop a new drug for ovarian cancer.

The story of oxaliTEX, a new drug that may one day achieve great victories over ovarian cancer, is double-stranded. It involves two pioneering researchers from two great Texas institutions weaving together their expertise in chemistry and biology. It builds on the failure of older generations of two drugs to fulfill the promise they once seemed to have. And it’s about DNA, that double-stranded structure that makes life possible.

Even the name of the drug tells this double story. The “oxali” comes from oxaliplatin, a platinum-based drug that’s very good at persuading tumor cells to commit suicide, if only it can navigate around the cell’s defenses to get to its DNA. The “TEX” comes from texaphyrin, a molecule developed at The University of Texas at Austin that tumor cells like to gobble up.

The story begins, sort of, at a small meeting held in Houston in 2008. The point of the meeting was to facilitate collaboration between two sets of researchers interested in drug development: the Texas Institute for Drug & Diagnostic Development (TI-3D), based at The University of Texas at Austin, and the Center for Targeted Therapeutics at the

University of Texas M.D. Anderson Cancer Center in Houston.

Researchers were invited to apply for two-year grants of up to $100,000 to fund a collaborative project.

Zahid Siddik, a professor of medicine (pharmacology) at M.D. Anderson, came to the meeting to find someone who could help him compensate for a key weakness in oxaliplatin, the chemotherapy drug that he’d been researching for almost a decade.

“If oxaliplatin can get to the nucleus of the cell and interact with the tumor’s DNA, it generates the kind of genetic damage that leads to programmed cell death,” said Siddik. “And it uses a different DNA damage pathway than the other platinum drugs, which is important, because there are a lot of tumors that are resistant at the molecular level. The tumor cells are too good at shutting down the uptake or increasing the efflux. So, oxaliplatin was too easy to keep out or flush out. We needed a way to overcome that resistance.”

Siddik had once believed that oxaliplatin would be a big step forward in treating these resistant types of ovarian cancers. However, the transport problem had proven too significant. Oxaliplatin is used in the treatment of some cancers, but not ovarian cancer, which has a five-year survival rate of 44 percent, and only 20 percent if the cancer isn’t caught early and is resistant to platinum drugs.

Finding Sessler

Siddik left that meeting in Houston without finding the right collaborator. Soon after, however, he got a call from Jonathan Sessler, professor of chemistry in the College of Natural Sciences at UT Austin and one of the founders of TI-3D.

The two men had missed each other at the meeting, but Sessler later heard through the grapevine about Siddik’s research. He thought they might be able to help each other.

Sessler was just coming off his own experience of disappointed drug expectations. He’d been working for years on the development of a drug based on Texaphyrin, a very large porphyrin molecule he’d synthesized. The drug had shown great promise in the treatment of certain brain tumors, but in December of 2007, after the third phase of clinical trials, the FDA had rejected it.

The rejection was a blow on a number of levels. It was financial. The stock of the company Sessler had co-founded around the drug, Pharmacyclics, plunged after the announcement. It was personal. As a cancer survivor himself, Sessler had invested hopes, now dashed or at least deferred, that his drug would soon make a difference in the lives of others with cancer.

And it was just bad luck, compounded by inexperience. The drug appeared to work. The Texaphryins were unusually attractive to brain metastases caused by lung cancer. They pooled inside the tumor cells and rendered them more vulnerable to radiation therapy and chemotherapy drugs. It appeared to improve significantly the condition of many of the patients in the trials. Unfortunately, Sessler and his partners had made some mistakes in how they’d designed the protocols for the clinical trials. As a result, the data ended up being skewed by two out of the 64 sites where trials had been conducted.

“In retrospect we should have written the protocol better or included more patients to overcome the statistical aberration,” he said.

Even before the drug was rejected, Sessler had been aware that it might be useful for fighting cancer in other ways. Because the Texaphyrin molecule was intrinsically attractive to tumor cells, it could be a carrier for other drugs, a kind of Trojan horse that would deceive its way into tumor cells. This was a property that Sessler remained convinced could be useful.

“Nobody really knows why, but rapidly proliferating cells, including tumor cells, like to bring in big molecules, and porphyrins, which are the pigments of blood, are big,” said Sessler. “Texaphyrin is a Texas-sized porphyrin. It is even bigger than the normal porphyrins found in blood. So, the hope was that it would be even more attractive. It’s saying to Mother Nature, ‘Oh, you came in for the $29.95 vacuum cleaner, but we just happen to have a floor model on sale that’s bigger and more powerful that will do the stairs even better.’”

After the FDA rejection, Sessler and his lab began actively looking for ways to use Texaphyrin in this other way. When he heard that Siddik had a drug in need of a Trojan Horse, he got in touch.

Oxaliplatin meets Texaphyrin

The two researchers talked and agreed to submit a proposal for one of the two-year grants, asking for funding to support the development of Texaphyrin-platinum “conjugates.” It was approved, and then later supplemented by a $1.3 million grant from the Cancer Prevention & Research Institute of Texas (CPRIT). Now the initial results are in, and they’re exciting.

The new drug, which combines the Trojan Horse qualities of Texaphyrin with the DNA-damaging powers of oxaliplatin, is dramatically more effective in killing ovarian cancer tumor cells that are resistant to the effects of platinum drugs. The five-year survival rate for patients with this type of tumor, if it’s not caught early enough to just surgically excise the entire tumor, is about 20 percent.

Siddik and Sessler think the survival rate for these patients would be doubled if the oxaliTEX results in cultured tumor cells can be reproduced in animal models, and then ultimately in humans.

What oxaliTEX does is what Siddik, Sessler and postdoctoral researcher Jonathan Arambula hypothesized it would, along with a few unexpected benefits. Thanks to the Texaphryin carrier, oxaliTEX is absorbed into the nucleus in much greater quantities than other platinum drugs. Once inside, it’s able to damage the cell’s DNA in a way that evades the tumor cells’ resistance. And for reasons the team doesn’t fully understand, it’s less toxic than either Texaphryin or oxaliplatin alone.

“The animals are able to handle seven and a half times more platinum in the form of oxaliTEX than oxaliplatin,” said Arambula, who’s been in charge of synthesizing and developing the drug. “Possibly more. We just stopped at that dosage. And oxaliplatin itself is much less toxic than cisplatin to the kidney.”

The combination of these qualities could be revolutionary not just in treating the resistant tumors, but the sensitive ones as well, since much more of the drug could be given before inducing irreversible side effects. It may also be applicable to other cancers, like mesothelioma and non-small cell lung cancer, which show the same kinds of resistances to other platinum drugs.

The current phase of the research involves testing the drug on tumors in mice. These studies are ongoing. If successful, the team will try to interest a pharmaceutical company in doing human trials.

“It’s always a long shot when you’re talking about anti-cancer drugs,” said Siddik. “The success rate is four to six percent. But I’m extremely optimistic. I’ve never seen in vitro data like this.”

For Sessler, success in developing a drug to help victims of cancer would be a personal as well as scientific triumph. As a former patient and tireless researcher, he has been combating the disease his whole adult life.

“It would be great to make progress so we don’t have to fight cancer quite so hard,” he said.

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Friday, 18 September 2020

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