Gaining Ground: Personal Losses Help Drive Pioneer in Stem Cell Study

Photo courtesy of Drew Donovan.

Jenny C. Chang, MB BChir, MD

Cancer took Jenny Chang’s aunts. It took her uncles. And it took her 9-year-old cousin.

In all, at least seven of her relatives died of cancer, and many of them stayed with Chang’s family as they underwent chemotherapy in the 1970s and the 1980s.

It was a troubling experience for a child.

“It was really grim,” recalled Chang, MB BChir, MD, now a renowned breast cancer oncologist and translational researcher. “In one sense, it was fascinating to understand that this alien could take over a body, even in a child, while, obviously, the human side was a tremendous suffering.”

Despite her youth and her family’s “hush-hush” attitude about the disease, Chang deduced that such suffering “could be alleviated–you just have to figure out what happened.” By the time she was 12, she had vowed to dedicate her career to doing just that.

Paving the Way for New Therapies

Today, the 49-year-old physician is well on her way. As director of the Methodist Cancer Center at The Methodist Hospital in Houston, Texas, Chang treats patients with breast cancer and conducts laboratory research in an area she has pioneered: studying the mechanisms of cancer stem cells, also known as tumor-initiating cells (TICs)⎯which, her investigations have shown, can survive chemotherapy, radiation, or hormonal therapy, and then spark recurrences or metastases. To help translate that work into practice, Chang also investigates treatments designed to target those cells, and leads early-stage clinical trials of the drug candidates.Largely, the doctor’s work has helped change the direction of breast cancer research by identifying potential targets for new cancer therapies.

In addition to isolating and patenting a 493-gene signature of the cancer stem cells that drive the “claudin-low” molecular subtype of breast cancer, Chang found evidence that such cells can be quieted through the targeting of specific molecular pathways, including the Notch pathway.

Her studies have demonstrated that targeting insulin-like growth factor can fight resistance in triple-negative breast cancer; that activation of the PI3 kinase pathway is associated with trastuzumab resistance; and that hyperthermia sensitizes resistant cancer stem cells to radiation. Chang has also found promise in targeting the STAT3 oncogene, which helps renew TICs in tumors that overexpress the protein p-Stat3. Before the end of the year, she said, her team will launch clinical trials of a small molecule, C188, designed to target the oncogene.

The doctor is already in the clinic as an investigator of chloroquine, a “cheap, safe” 60-year-old malaria drug being repurposed for use in breast cancer, and of the gamma secretase inhibitor MK-0752, which targets TICs and is being tested in metastatic breast cancer. In a phase I/II study, MK-0752 “worked well in decreasing cancer stem cells,” the doctor said, and another trial is being planned.

In short, Chang is unraveling the mysteries of cancer drug resistance that have, for so long, baffled oncologists, researchers, and patients.

Taking Cancer Center’s Helm

“We know so little, but we’re beginning to know a lot more, because with the ability of high-throughput transcriptors and different types of profiling, like Next-Gen sequencing, we can understand some of the pathways that drive the tumors,” Chang said. “Over the next 10 years, the amount of data we’ll know about cancer will just be exponential, and putting it into perspective in a clinically relevant way that impacts patients is where I’d like to focus, because I see it as the most important thing.”Chang has been conducting her research at The Methodist Hospital since October 2010, when she stepped into the role of director of its cancer center.

She made the move from Baylor College of Medicine, also in Houston, where she began as an assistant professor in 1999 and rose to the rank of professor. While the institutions were integrated when Chang joined Baylor, they are now independent of each other.

For Chang, the switch included moving her large lab–including about five PhDs and four technicians–to Methodist’s new building.

It has also meant becoming the force behind some big changes.

Probably the most major shift has involved establishing a clinical research program at the cancer center. When Chang came on board, there were phase III, pharmaceutical-driven studies being conducted there, but trials arising out of academic research are something new.

Now, for example, “we have about 25 breast cancer trials open, a range of investigator-initiated, federally funded studies,” said Chang, who has seen to it that the center recruited top geneticists to drive such work, and ultimately wants trials to take place in all five of Methodist’s Houston-area hospitals. “We can offer our patients a trial that best suits them.”

During the same time period, Chang has overseen the addition of chemotherapy infusion centers–complete with physicians– to each of the five hospitals, so that patients don’t have to travel far to receive their cancer treatments.

“Healthcare is changing to become more integrated,” she said. “In larger organizations, offering start-to-finish healthcare delivery is what it’s going to be about. This was an opportunity to build something from the start. Now, Methodist has the whole continuum of care.”

The doctor is also proud to say that her cancer center boasts one of the country’s only multidisciplinary triple-negative breast cancer clinics, which provides a “one-stop shop” for patients who need diagnosis or treatment.

“Triple-negative breast cancer is the final frontier,” Chang said. “We don’t have good treatments against it, only chemotherapy, and cancer stem cells are usually triple-negative cancer cells. So that’s why figuring it all out is going to be fun.”

Away from her desk, Chang, who serves as a professor of Medicine at Weill Cornell Medical College, Methodist’s primary academic partner, makes time to teach medical residents and fellows, as well as to give an array of national and international lectures.

Jenny C. Chang, MB BChir, MD . . .

• Is the legal guardian of two boys. One is in high school, the other is in college.
• Enjoys running marathons, but recently underwent surgery for an injured knee. “My orthopedic surgeon said, ‘You’ll never run again,’ but I’m going to,” Chang said. “I’m still very hopeful.”
• Cites The Emperor of All Maladies: A Biography of Cancer, by Siddhartha Mukherjee, MD, as her favorite book. “It takes us back through the history of cancer and reveals how little we actually know about this really horrible disease,” she said. “It’s a very humbling book.”
• Is passionate about getting cancer care to patients who can’t afford it. Chang has an ongoing grant from the Komen Foundation to facilitate breast cancer prevention and treatment for underserved and minority women, and has received grants from the Avon Foundation to create a “safety net” for the medically underserved in one Texas county. “In Houston, 30% of the population has no health insurance, and in certain areas, among Hispanics, 50% are uninsured,” she said. “Since I took on my new job, I’ve started the Denver Harbor Clinic for the underserved and indigent. We find funds from multiple sources, including Methodist’s charity-care fund, to sponsor the whole treatment of these patients for breast cancer.”
• Has received about 40 grants to support her research, including $1.5 million from the National Institutes of Health/National Cancer Institute to target Notch, PI3-AKT, and other novel pathways in breast cancer stem cells.
• Has served on numerous professional committees, including participation as a member of the Scientific Program Committee of the American Society of Clinical Oncology, and as an executive member of the Grants Selection Committee of the Conquer Cancer Foundation.
• Holds an endowed chair at Methodist, and held one previously at Baylor College of Medicine.
• Was honored at the “Unmasking the Unsung Heroes” event in Houston in 2009, and was included, in 2011, on US News & World Report’s list of Top Doctors.

Idealism Sparked Career

And, she spends two days each week treating breast cancer patients, many of whom impress her with their courage and goodwill. The very first patient to join the hospital’s ongoing trial of trastuzumab emtansine (T-DM1) in HER2- positive breast cancer, Chang said, is a Methodist pastor “who came in with the willingness to help everybody else. Her attitude is just wonderful.”Born and raised in Singapore, Chang came from a well-to-do family with an ethic of responsibility.

“My grandparents, especially on my mother’s side, were very much into helping people who were less fortunate,” she recalled. “That was instilled in us at an early age.”

It was that idealism, combined with her loss of so many loved ones to cancer, that convinced Chang to pursue a career in medicine. Nearly 40 years and 100 published papers later, the doctor’s views haven’t changed a bit.

“I do believe you should not be a doctor unless you want to help people,” said Chang, who has spearheaded several efforts to provide medical care to underserved patients who have cancer.

The doctor’s dream did not get off to an auspicious start. Until her teenage years, she recalls being mischievous and unfocused as a student. At one point, she said, “I turned off all the electricity in the school because I wanted to get out early.”

Chang jokes that her behavior was responsible for her mother’s decision to send her outside Singapore to attend college. Once there, though, the doctor made up for lost time.

A premed major at the University of St. Andrews in Scotland, Chang earned her MB BChir at Cambridge University in 1989, and then went on to earn a research doctorate at the University of London, focusing her studies around breast cancer. She took on the additional course of study because she wanted to learn as much as possible about the disease she planned to spend her career fighting.

Fulfilling a Dream

“There are two types of doctors: those who believe the treatments that are available are the best and only things there are, and those who believe the glass is half empty, that there’s always more to know, that paradigms have to be changed,” Chang said. “I believed that, unless you could cure cancer, it was half empty. I’m optimistic that we will make inroads in the treatment of breast cancer, but I’m also very aware that there are many things we do not know.”Chang served as an intern and resident in internal medicine at Cambridge and the University of New South Wales in Australia, and then, in 1996, completed a fellowship in medical oncology at Royal Marsden Hospital at the University of London. Her research fellowship was in the laboratory of Mitchell Dowsett, PhD, now professor of Biochemical Endocrinology in the divisions of Breast Cancer Research and Molecular Pathology, and Trevor J. Powles, MD, PhD, emeritus professor of Breast Oncology, both at the Institute of Cancer Research in England.

After completing her education, Chang spent several years working as an assistant professor at National University Hospital in Singapore. She had been promised a job at Baylor College of Medicine, she said, and wanted to spend time with her mother while waiting for that work to start.

Upon moving to Texas, Chang experienced some culture shock.

“Texans are more socially conservative compared to the people in London, by far,” she said. “But, having spent the last 13 years here, I know that a Texan is always extremely honorable. They really believe in their work ethic, and they look after their fellow Texans.”

From the start of her career, Chang’s work was focused on prognostic and predictive markers in breast cancer.

In a 2007 paper, she presented the results of an RNA interference screen, identifying a set of genes that makes cancers sensitive to treatment with paclitaxel; she simultaneously identified a ceramide transport protein–COL4A3BP, or CERT– that causes resistance to the chemotherapy (Cancer Cell. 2007; 11[6]:498-512).

Under the Microscope:

Two Recent Projects Arose From Discovery of Breast Cancer Gene Signature

Jenny C. Chang, MB BChir, MD, broke new ground in cancer research when she identified and patented a 493-gene signature for breast cancer. Two of her latest projects involve silencing those genes to help reverse breast cancer recurrences and metastases. In this interview, she provided an up-close look at these yet-to-be-published projects.

 

Q: You, together with others at The Methodist Hospital Research Institute, received a $2.37 million grant from SAIC-Frederick, Inc to investigate multistage vectors for the delivery of siRNA therapeutics. Can you discuss some of the details of that work?

A: Working with Bhuvanesh Dave, PhD, and the rest of the team, I started with the 493- gene signature and used a mammosphere-forming efficiency assay to whittle that down to two genes, not previously known to be involved with cancer, that appear to be critical to tumor initiation and metastases. I’m in the process of patenting those genes now.

This understanding could lead to new clinical therapies in the long run, if we have a good mechanism of delivering them to humans. That’s why we’ve been exploring the use of siRNAs.

siRNAs are 21-nucleotide pieces of RNA that silence the messages carried by mRNA with laser-like precision, so that a targeted gene cannot be active anymore. In this case, when we removed the messages of the two genes in question in the in vivo setting, we saw a reduction in both tumor size and metastases. This is promising because the biggest issue in breast cancer, especially in triple-negative breast cancer, is relapse, and our data show that this technique, in combination with standard-of-care chemotherapy, could help reverse that. While most of our evidence is in triple-negative breast cancer, we would expect this to work in all treatment-refractory breast cancers.

Although siRNAs have been used in clinical trials, there is no FDA-approved, clean vehicle for delivering them into patients. My lab will be involved in developing such a vehicle and, hopefully, testing it in phase I and II trials. We expect it to have a nanoparticle base and to be given by IV injection. The advantage of packaging vectors is that they will allow the RNA to either quickly target a tumor or stay in the body for a long time, making for a better therapeutic module. We will be doing this work in collaboration with Mauro Ferrari, PhD, president and CEO of The Methodist Hospital Research Institute and a founder of nano/microtechnology.

Our research involving the two isolated genes has also included investigations of the molecular pathways in which the two genes may be working, so we can understand their mechanisms in metastasis. While siRNA is one way to target, we can also target other pathways, and maybe there are inhibitors already approved that will accomplish that. Our goal is to figure out the quickest route from bench to bedside.

Q: You have helped run clinical trials of the gamma secretase inhibitor MK-0752, which targets tumor-initiating cells, in patients with metastatic breast cancer. What kinds of results have you seen, and what will be the next steps in developing this compound?

A: This project also arose from my 493-gene signature of breast cancer. With my lab’s senior director, Melissa D. Landis, PhD, and the rest of my team, I conducted an analysis on the signature to identify important signaling pathways, and found that the top one was a Notch signaling pathway. I knew of a small-molecule inhibitor, MK-0752, that was available from Merck and was designed to inhibit that pathway, so we began testing it in the lab in patient-derived xenografts, in combination with docetaxel.

At the same time, we participated in a correlative clinical trial that looked at the dosing and safety profile of the oral compound in 30 patients. The trial was carried out at the University of Michigan Comprehensive Cancer Center, Dana-Farber Cancer Institute, and Baylor College of Medicine, which was our site at the time. We found that the compound was well tolerated.

We also looked at how MK-0752 affected cancer stem cells by analyzing three biopsies each–taken at baseline, at 21 days, and at the end of treatment–provided by six patients in the trial. While the results weren’t statistically significant, they were promising when it came to reducing stem cells.

The key as we go further into these trials–another is being planned–is to determine if certain subtypes respond to this therapy. Because we’re targeting cancer stem cells, and because triple-negative breast cancers are considered to have more of these cells, patients with that disease might be optimal candidates.

A Focus on Cancer Stem Cells

Using high-throughput molecular profiling, Chang has also identified and patented patterns of gene expression that predict for both sensitivity and resistance to docetaxel.In 2008, Chang presented her first evidence that “tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44+/CD24-/low) may be resistant to chemotherapy and therefore responsible for cancer relapse” (J Natl Cancer Inst. 2008;100[9]:672-679).

A good deal of her work since then has focused on silencing such cancer stem cells.

In her 2010 study on hyperthermia to target treatment-resistant TICs in mouse models, Chang delivered the therapy after radiation, “using intravenously administered, optically activated gold nanoshells.” The technique sparked a “reduction in tumor size without a concomitant increase in the percentage of cancer stem cells,” the doctor and her colleagues reported (Sci Transl Med. 2010;2[55]:55ra79).

In addition, after identifying the oncogene STAT3 as critical to the self-renewal of some cancer stem cells, Chang discovered and created the small-molecule drug C188 and found that it decreased TIC markers and mammosphere formation in tumors that overexpress p-Stat3, improving recurrence-free survival fourfold in mouse models in comparison with docetaxel alone. Her team plans to begin testing the treatment in humans very soon.

Related work is built on Chang’s finding that cancer stem cells are affected by epithelial-mesenchymal transition (EMT), a process that alters the cells to promote cancer progression and invasion into the surrounding microenvironment. Once “recruited” to distant organs, the cancer cells undergo mesenchymal-to-epithelial transition (MET), which accelerates metastases, the doctor added in a study published this year (Cancer Res. 2012;72[19]:4883-4889).

“Targeting specific molecular pathways, such as Notch, Wnt, and TGFβ–in addition to conventional chemotherapy and radiation therapies that target the bulk tumor– may ultimately provide a more effective strategy in treating breast cancer,” the doctor and her colleagues wrote in 2010.

Learning from Life

Exploring yet another pathway, Chang and colleagues recently reported that highdose temsirolimus, when “combined with the brain penetrant MEK inhibitor SL327,” significantly reduces brain metastasis in triple-negative breast cancer in in vivo models. The combination also “prohibited perivascular invasion of tumor cells and inhibits tumor angiogenesis,” the researcher and her coauthors wrote (Breast Cancer Res Treat. 2012;131[2]:425-436).Over the years, Chang’s work has been both engrossing and time-consuming, resulting in sacrifices and stress on personal relationships, “as with most people who work too hard,” the doctor said.

Chang tries to look at such difficult experiences as an opportunity to learn. It’s the same concept, she said, that Rudyard Kipling describes in his poem “If.”

“Triumph and disaster are the same,” the researcher said. “From your disasters, you have to learn to pick yourself up and figure out what the issues are, and when you have triumphs, we all know they’re usually short-lived and you need to move on.”

Determining how to cure cancer is the same kind of endeavor, Chang added. “It’s always a continuous remodeling and understanding of the processes that drive the disease,” she said.

Despite all the mysteries their work has yet to uncover, Chang is optimistic that she and her fellow researchers are on the cusp of enormous progress in fighting cancer.

“We’re very close to curing HER2-positive breast cancer,” she said, “and I think it’s possible that we’ll cure breast cancer as a whole within my lifetime.”