Dr. Maureen Murphy says her first professional goal was to become a nun. She grew up going to Catholic school in Sussex County, New Jersey, but decided “there was something inherently wrong with the patriarchal way that religion went.”
Her second goal was to cure cancer.
Murphy did her undergrad in biochemistry and English at Rutgers, got her PhD in molecular biology at Penn, did her post-doctoral research at Princeton, and then became a professor at Fox Chase Cancer Center, where she worked for 14 years before coming to the Wistar Institute, an independent biomedical research center tucked into the heart of University City. She’s also an adjunct professor at Drexel’s College of Medicine, as well as Penn’s Perelman School of Medicine. She’s passionate about writing, too, and teaches it to graduate students and post-docs, with an emphasis on collaborative peer review.
Now, seven years after arriving at Wistar, Murphy faces the realization of her childhood dream. She runs a lab that has developed a drug with the potential to save thousands of people with a kind of melanoma (a dangerous cancer) that currently has no cure if it isn’t caught early.
The Institute houses 32 laboratories run by an international cohort of 289 staffers and 58 post-doctoral fellows. Its labs specialize in cancer, vaccines, and immunology. We can thank Wistar for the research behind several important vaccines, including rabies, rubella, and rotavirus (an often-deadly diarrheal illness).
In today’s scientific landscape, the independent Wistar is “a dying breed,” says Murphy. It has survived in part because of its “very active technology transfer and patenting office.” That means turning research into real treatments, like the drug Remicade, for autoimmune disorders.
The road from the lab to the pharmacy is often tougher than even the most brilliant scientists realize, and that’s where the Science Center’s QED Proof-of-Concept Program, which has been partnering with Murphy over the last six months, comes in.
QED (for the Latin quod erat demonstrandum, meaning “proven as demonstrated”) helps to commercialize promising research with legal, marketing, and business development support, as well as grant dollars—in other words, get revolutionary research from lab to patients. In addition to practical support from QED, Murphy just received a $100,000 grant (matched by Wistar for a total of $200,000) to help take her melanoma-targeting drug to the next step. It’s Wistar’s first QED award.
With six out of 32 scientists working on it, Wistar is “the number-one place in the world to study melanoma,” Murphy explains. And for too many people, melanoma, while relatively rare, is a death sentence.
We have three main types of skin cells (squamous cells, basal cells, and melanocytes), and they’re each susceptible to a different type of cancer. Melanoma, starting in melanocytes (which produce the pigment that protects us from the sun), is the rarest of the three. According to the American Cancer Society, it accounts for only about one percent of skin cancers, but causes a large majority of the deaths from skin cancer. The average age for a melanoma diagnosis is 63, but it’s also one of the most common cancers for young adults.
We can cure the earliest stage of melanoma, Murphy explains, by surgically removing the spot where the tumor expands its circumference on the skin’s surface. But if you don’t catch it in time, it starts to grow vertically, penetrating the skin and then spreading to lymph nodes and organs (this is called metastasis). At that point, the prognosis is “dismal,” Murphy says. These patients “have a less than 10 percent chance of living five years.”
That’s partly because melanoma can be caused by different cellular mutations. One, known as BRAF mutant melanoma, is treatable. Another, known as NRAS mutant melanoma, resists all treatment. Murphy and her partner, medicinal chemist Dr. Joe Salvino, want to change that.
The key? Mitochondria: the tiny bio-machines inside our own cells, producing the energy we need to live and grow.
Mitochondria are the next frontier in cancer treatment
Our cells multiply through the power of our mitochondria. However, Murphy notes. “What most people don’t know is that the average cells in your body are not dividing.” They’re generating energy, not proliferating. But cancer cells are. They’re dividing like crazy.
Research over the last few years has revealed that “tumor cells are exquisitely reliant on mitochondria. Especially drug-resistant tumor cells,” says Murphy. If we could move from targeting the cells themselves that are dividing (as in current forms of chemotherapy) to shutting down the mitochondria that are powering the cancer cells, we could stop the disease in its tracks.
The key to Murphy’s drug is a protein known as HSP70, and we’ve actually been using it to spot cancer for decades. “I always say HSP70 is the best cancer target in the world, because it’s a stress-induced protein,” Murphy says. It shows up only when a cell doesn’t have enough oxygen or growth factors. And tumor cells, on their deadly mutant mission to divide, “constantly are starving.” So they’re full of HSP70.
When Murphy and her lab started this project in 2009, they developed a protein-inhibitor drug that targeted HSP70 in the cell. But while they were working on that, “we noticed an awful lot of the HSP70 is at the mitochondria.” In 2014 her team generated an HSP70 protein inhibitor that targeted the mitochondria.
HSP70 is vital here: It helps the proteins inside the mitochondria stay properly folded, and when you block HSP70, things get screwy. The mitochondria metabolism shuts down, and the melanoma cells lose all the energy they need to divide. Murphy’s Wistar drug stops NRAS melanoma tumors in mice.
As a scientist with a potentially revolutionary drug on her hands (in the lab, it has also been effective against B-cell lymphoma, multiple myeloma, and squamous cell carcinoma), she now faces a daunting reality: It costs millions to bring a drug out of the lab into clinical trials, and if you can’t find the funding, you’ll never bring the drugs to market.
“Good drugs die because you don’t have enough money to get them there,” she says.
The drug is effective in mice, but the team doesn’t know how it’ll act somewhere else. For example, does it degrade in the human body? Is it metabolized in the liver? Does it have any dangerous side effects?
The QED program has helped Murphy with tools outside the lab. The pharmaceutical industry, and all the fundraising, patents, and marketing that must happen along the way, can bewilder a scientist. For example, a QED lawyer helped her understand the counter-intuitive truth about patents. Not only do you have to demonstrate your compound is effective. You have to demonstrate that the discovery is peculiar and difficult to find by logical means. For example, you could illustrate a closely related compound that’s not effective.
“That’s non-obviousness, and therefore no-one else could have thought about it. Isn’t that the wildest thing you ever heard?” Murphy marvels of the patenting process. She says starting the path toward clinical trials is like being above the water by a desert island, and suddenly getting a snorkel mask that lets you see the teeming coral reef hiding below the surface.
“I never would have thought to myself, what’s the business market for NRAS mutant melanoma?” Thanks to QED advisors, she learned it’s what’s called an “orphan market,” with no other drugs in the wings, and therefore attractive to big pharma.
So far, her drug seems most effective on NRAS mutant melanoma, but more testing is needed to confirm that. The matched QED grant will help Murphy move on an Investigational New Drug filing with the FDA, a crucial first step to clinical trials. They’re also working on “synergy assays,” in which tumors in the lab are treated with the new drug as well as approved drugs, to find out if any of the pairings are more effective than either drug would be alone.
If the latter is true, then they might be able to partner with an existing pharmaceutical company to fund trials. Or Murphy and Salvino will need to launch and fund their own company to bring the drug to market—a decision Murphy says must come in the next six months.
“There’s still a lot of work that has to be done, and it can’t be done in an academic lab like this.” The woman who didn’t become a nun is up to the challenge.
This article was produced as part of our Writer in Residence Program with the University City Science Center.
This article was updated for clarity on July, 10, 2018.