Exploring Tumors in Context: Jain's Work Blazes Trail on Microenvironment

Photo courtesy of Massachusetts General Hospital Photo Lab

An Interview With Rakesh K. Jain, PhD

When Rakesh K. Jain, PhD, joined the field of cancer research, most experts believed that knowing everything possible about cancer cells was the sole key to a cure.

Yet Jain was convinced that the abnormal microenvironment around a tumor was also a big part of what fueled a cancer, and needed to be considered when treating the disease.

Few were interested in his opinion.

As a young assistant professor of Chemical and Biomedical Engineering at Columbia University in the mid-1970s, Jain’s first six requests for research grants, all focused on the role of tumor microenvironment in drug delivery and efficacy, were rejected.

When a decade passed and the idea still hadn’t really caught on, Jain decided he needed to teach anyone who would listen, one by one, no matter how long it took. So he launched what he believes was the first course on tumor microenvironment at any university in the United States or abroad, an intensive week-long class that began with an enrollment of just a handful of students but has since moved to Harvard University, along with the doctor, and become extremely popular.

In the meantime, Jain, who is the Andrew Werk Cook Professor of Tumor Biology (Radiation Oncology) at the Harvard Medical School and director of the Edwin L. Steele Laboratory for Tumor Biology at Massachusetts General Hospital (MGH), has helped drive major advances in the understanding of tumor pathophysiology.

His work involves normalizing tumor vessels and microenvironment so that cancer medicines such as chemotherapy, radiation, and immune therapy can be better delivered and more effective. An important way to achieve that, he has found—although it seems counterintuitive— is through the use of antiangiogenic agents, which were designed to starve tumors but, at low doses, actually help normalize their chaotically organized and leaky blood vessels.^1,2 The first to discover the antiangiogenic properties of trastuzumab, Jain’s lab also works to identify biomarkers meant to better guide the use of such therapies.

To facilitate that work, Jain and his colleagues have developed an array of imaging technologies, innovative mathematical models, and sophisticated animal preparations— including the implantation of transparent windows into mice to allow direct observation of tumors, the genes within them, and the host stroma around them.

Last year, all of that work came full circle, gaining resounding recognition when Jain received the Science of Oncology Award given by the American Society of Clinical Oncology (ASCO). It was an indication that Jain is now regarded as a pioneer in oncology for integrating the principles of engineering with biology to improve treatment and creating a unique approach to cancer research.

Building that wide acceptance of the importance of tumor environment has sometimes been frustrating, the 62-year-old scientist acknowledges.

Busy but Joyful Days

“New music or art is not usually accepted right away, so why should it be different for science?” Jain asked. “As much as we’d like to be impatient and say, ‘Why don’t they get it?’ it’s human nature.”It’s inside the Steele Lab, a division of about 80 scientists and support staff, that Jain continues to push his research forward, working most closely with a group of four assistant professors, four associate professors, and a cadre of fellows, graduate students, and technicians from diverse disciplines including engineering, mathematics, physics, chemistry, molecular and cellular biology, genetics, immunology, pathology, radiology, radiation, medical oncology, neuro-oncology, pediatric oncology, and surgical oncology.

At the same time, the doctor is “tightly engaged” as a scientific leader of clinical trials—22 in the last decade, all dedicated to finding biomarkers for the success of, or resistance to, antiangiogenic therapies in the treatment of various malignancies and some nonmalignant tumors, such as schwannoma.

“I’m not an MD, so I don’t conduct trials myself, but we are very much involved in designing these trials and analyzing the resulting data, interpreting it, and helping to use that information to design new preclinical and clinical studies,” Jain said. “In all of these trials, the biomarker work was done in the Steele Lab, which is renowned worldwide for its translational research.”

At this stage of his career, Jain’s colleagues and students are often surprised to find that he spends little time traveling to conferences to lecture or present study results. While Jain previously dedicated a lot of time to such activities, he decided a decade ago to limit his trips out of town to about a dozen a year.

“Ten years ago, we were very blessed to have twin daughters,” Jain said of himself and his wife, Jacqueline Anne Samson-Jain, PhD, assistant professor of Psychology at McLean Hospital, a Harvard Medical School affiliate. “We both decided we’d done enough traveling, and it was time to stay home and spend time with our kids. I’m very happy for it. It helps my personal life to spend time with family, it helps my lab because my colleagues see me any time and all the time, and it helps my physical health. It’s a win-win situation.”

But Jain still takes the time to plan and teach his annual, weeklong course on tumor pathophysiology, titled “Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers.” As an extension of the course, he also teaches a semester-long graduate class on tumor pathophysiology, open to students from both Harvard and the Massachusetts Institute of Technology.

Rakesh K. Jain, PhD...

• Is the oldest of 10 children, five boys followed by five girls. Among them are twin sisters, and now Jain and his wife are the parents of twin daughters.
• Loves to read everything from Robert Ludlum spy novels to books about sociology like The Tipping Point, by Malcolm Gladwell, to tomes about oncology such as The Emperor of All Maladies: A Biography of Cancer, by Siddhartha Mukherjee, MD.
• Is a movie buff who likes films of all genres by a variety of directors from around the world. “In India, when I was growing up, my parents used to take us to a movie once a week, and I’ve maintained that tradition pretty much my whole life,” he said. “I don’t like watching movies on TV as much. I like to have the whole experience of the theater.”
• Loves music, particularly opera. “When I was on the faculty of Columbia University, I often went to the Metropolitan Opera,” he recalled. “They had standing-room tickets for $10, and you could stand in the back row for the entire opera with a magnificent view.”
• Enjoys art, and tries to visit a museum whenever he’s in a new city.

• Swims three to five days per week.
• Has published 575 papers, which have been cited more than 54,000 times.
• Is a member of three US National Academies: the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine.
• Has long been involved in the work of the American Association for Cancer Research, currently as a member of its Special Conferences Committee.
• Has won an array of awards and distinguished lectureships. Recent honors include the Rous-Whipple Award of the American Society of Investigative Pathology; the American Cancer Society/Society of Surgical Oncology Basic Science Lecture; the Breast Cancer Research Innovator Award given by the US Department of Defense; the Science of Oncology Lecture/Award of the American Society of Clinical Oncology; and being named by Forbes India magazine as one of the “18 Indian Minds Who Are Doing Cutting Edge Work.”

Starting Small

Twenty-eight years ago when Jain was a professor at Carnegie Mellon University in Pittsburgh, Pennsylvania, his intensive class started out as a rarity, and not only because it was a medical course in a department of engineering. It was also the only course of its kind at any university anywhere, Jain believes, and was especially needed because there were no textbooks available on the topics it covered.

In its infancy, from 1986 to 1991, the weeklong course consisted of sixteen 90-minute lectures over four days by Jain and his late mentor, pathophysiologist Pietro M. Gullino, MD. After Jain and the course moved to Harvard and MGH, a rotation of distinguished faculty members, beginning with Judah Folkman, MD, the founder of the angiogenesis field, began dropping in to teach, helping to make it one of the highest-ranked classes offered by the Harvard Medical School Department of Continuing Medical Education and MGH Department of Radiation Oncology.

Jain proposed the idea for the intensive course as Gullino was preparing to retire from the National Cancer Institute (NCI) and move home to Italy.

Gullino began making annual visits to “stay at my home as my guest and teach this course with me,” Jain recalled. “Only seven students showed up the first time, and Gullino looked at me and said, ‘I don’t think people are interested. Why don’t we just quit?’ I said, ‘Let’s try it one more time.’ The next year, 24 students came. The rest is history.”

Teaching the course has been fun, Jain said, while the effort also contributed to the scientific community’s knowledge about pathophysiology—much like Jain’s own career thus far.

Making Breakthroughs

“I’ve enjoyed all my faculty positions,” he said. “Columbia taught me a lot of things, Carnegie Mellon was a lot of fun, and this last 22 years at Mass General have been absolutely sheer joy.”Jain was at Carnegie Mellon in the mid-1980s when he had an “aha” moment that has shaped the rest of his career.

“One of my biggest breakthroughs came when I realized that solid tumors had high fluid pressure,” he said. “If you measure pressure in a normal tissue, it’s about zero millimeters of mercury. But in tumors, it’s 20 or 30 or higher. We developed a mathematical model to examine the implications of this high pressure and concluded, ‘This is bad news for the delivery of drugs, and may facilitate tumor progression.’ So our mission became to figure out why the pressure was high and how to lower it in patients.”

“A second breakthrough came in 2001, when I realized that the pressure in tumors could be lowered by normalizing blood vessels,” Jain continued. “The high pressure is a result of leaky blood vessels and collapsed lymphatics in tumors. Leakiness also contributes to sluggish blood flow in tumors, resulting in hypoxia. So I proposed to fix the leakiness by using antiangiogenic drugs. This idea was quite controversial, because the whole basis of antiangiogenic therapy at that time was to starve tumors by destroying their blood vessels, and I was suggesting the use of antiangiogenic agents to do the opposite— repair blood vessels so the tumor blood flow could be improved.”

In turn, those repairs were expected to alleviate the hypoxia that can fuel tumor progression and metastasis, restoring the oxygen level needed for the success of treatments including radiation, chemotherapy, photodynamic therapy, and immunotherapy, Jain explained.

His team proved the principle not only in the lab, but also in trials of patients with glioblastoma, whose survival improved only when the blood flow and oxygen levels in their tumors increased with the administration of antiangiogenic drugs.

As an outgrowth of that research, Jain and his colleagues were the first to prove that trastuzumab, designed to block HER2 overexpression on breast cancer cells, was a powerful antiangiogenic agent. Building on that knowledge, the team recently discovered not only that adding lapatinib to trastuzumab is helpful in fighting HER2-positive breast cancer, but that adding an anti-VEGFR2 antibody to the combination slows tumor growth in the brain, resulting in an additional survival benefit in mice.³

Indeed, a phase II clinical trial presented at ASCO’s Annual Meeting this year showed encouraging responses in brain metastases when patients received both trastuzumab and bevacizumab.⁴ Jain’s work has also led to treatment strategies with anti-VEGF therapies, for some nonmalignant diseases that involve abnormal vasculature, including neurofibromatosis-2.

Further, Jain’s group has identified specific biomarkers of resistance to the restoration of blood vessels via anti-VEGF therapies such as pretreatment soluble VEGFR1 or an increase in SDF1 alpha upon treatment, thus helping to define an area where new treatment options need to be studied.

In addition, in an attempt to normalize the extracellular matrix around tumors, his lab has proposed “the novel hypothesis that the anomalous assembly of the collagen network can prevent the penetration of therapeutic agents in tumors, and showed that the hormone relaxin, bacterial collagenase, and MMP-1/8 can improve drug distribution by modifying this network,” Jain wrote on his institution’s website.

Approaching the problem from yet another direction, Jain is working on a technique to engineer new blood vessels that last a patient’s entire life. The strategy involves generating endothelial and smooth muscle cells from human embryonic stem cells and induced pluripotent stem cells, and is moving closer to translation, Jain wrote in 2007 and 2008. Among the patients who may be helped through this technique are those who have ischemic diseases.

To observe the activity within tumors in real-time, Jain and his team members have developed and/or employed cuttingedge technologies including multiphoton intravital microscopy, second-harmonic generation microscopy, fluorescence correlation microscopy, optical frequency domain imaging, wide-field endoscopy, and quantum dot nanotechnology.

In conjunction, Jain relies on his novel strategy of surgically implanting transparent windows into genetically engineered mice, which he said “has provided unprecedented molecular, cellular, anatomical, and functional insights into the vascular, interstitial, and cellular barriers to cancer treatment.”

Looking ahead, Jain has goals besides tumor normalization in his sights. Over the next two decades, he envisions himself focusing on how to make therapies more affordable and more effective for patients.

Following His Talent

“Recently approved cancer drugs cost an average of $50,000 to $100,000 per patient per year in the United States, often for a survival benefit of months and not years, and 90% of the world cannot afford these drugs,” Jain said. “My research will focus on repurposing drugs approved for other diseases, or using drugs that are generic. I would like more patients to be able to afford cancer treatment and have a survival benefit longer than what the current drugs provide.”Jain grew up living a “fun, easy” life with his parents and nine siblings in 100,000-population Lalitpur, a “small town by Indian standards,” until he finished the eighth grade.

That was when his intellect became not only a gift, but also a responsibility.

Jain’s parents, wanting to nurture his abilities, sent him to live with an aunt in another state, where he attended a more elite high school than those available near his home.

“In those days in India, you could not call people easily on the telephone, and there were no cell phones,” he recalled. “The only way to communicate was by letters, and on holidays I would go home to visit my family. Then I would get three months off in the summer, and I used to spend that whole time with my family. That was how I made up for my lost time with the family during the academic year.”

Photo courtesy of Massachusetts General Hospital Photo Lab

Rakesh K. Jain, PhD, seeks to foster a cooperative environment at the Edwin L. Steele Laboratory for Tumor Biology, where is the director. Here, he works with Kamila Naxerova, BS, a graduate student.

When he graduated, Jain went on to attend the Indian Institute of Technology (IIT), in Kanpur, which he described as the home of the country’s top engineering program.

After graduating in 1972, Jain continued his education at the University of Delaware, where he earned his MS and PhD in chemical engineering. He served as an assistant professor of Chemical Engineering at Columbia University from 1976 to 1978 before being recruited to Carnegie Mellon, where he rose though the ranks and became a full professor in 1983. After a full-year sabbatical in Germany as a Humboldt Senior Scientist Award recipient, he moved to Harvard to take on the endowed professorship and direct the Steele Lab at MGH in 1991.

Jain’s journey to the United States was inspired, in part, by his experiences as an undergraduate. He knew that the University of Delaware had a top-notch chemical engineering department, but also dreamed of working with a particular member of the faculty there.

“When I was studying at IIT, many of my chemical engineering textbooks were written by Professor Morton M. Denn, PhD, of the University of Delaware,” Jain recalled. “I thought, ‘This guy must be very cool to work with.’ I ended up doing my master’s thesis with him on mathematical modeling of the Delaware River.”

Jain changed his focus to oncology in 1974, as he was finishing up his thesis.

“I thought, ‘Maybe I should do something different for my PhD,’” Jain recalled. Apparently, his PhD professor had the same idea. That mentor, James Wei, ScD, decided one day to drive Jain to the NCI, in Bethesda, Maryland, and introduce him to Gullino, then chief of the Laboratory of Tumor Pathophysiology there. Wei thought something good could come of the connection.

During their meeting, Gullino told Jain about his development of a tumor model in rats that was connected to the host with a single artery and a single vein, and soon the young engineer was using the model to conduct input/output analyses, injecting a drug into the artery and determining how much came out of the vein and how much remained in the tumor. He spent half of each week conducting the research at the NCI, and the remainder in Delaware, analyzing the data he had collected.

“The biggest shock came in 1974 when I did those experiments and discovered that most of the injected drug did not accrue in the tumor,” Jain said. “It dawned on me that drug delivery is a big problem in cancer—you can’t cure a disease if you can’t get enough drug in there. That’s what got me excited about this research.”

“When I realized this, I said, ‘OK, why don’t I devote my career to understanding why drugs don’t get into the tumor and how to improve their delivery and efficacy?’ And that’s how the whole thing began.”

Turning that epiphany into a widely embraced principle about cancer treatment has depended, in part, on an attitude Jain learned long before he became an engineer. In his lab, Jain has always tried to foster the kind of harmony he experienced in his parents’ household, where everyone pitched in to help and had fun in the process.

“Harvard is one of the most competitive environments in the world, but when you walk into our lab, you’ll see people cooperating,” Jain said. “What I say to them is quite logical and simple: ‘We are fighting a bigger enemy called cancer; why would you want to waste time fighting with each other?’ Apparently, they have embraced this philosophy.”

“It makes my lab a fun place to go to work every day. I look forward to it.”

References

1. Jain, RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers [published online ahead of print May 13, 2013]. J Clin Oncol. 2013; 31(17): 2205-2218.
2. Huang Y, Goel S, Duda DG, et al. Vascular normalization as an emerging strategy to enhance cancer immunotherapy [published online ahead of print February 25, 2013]. Cancer Res. 2013;73(10): 2943-2948.
3. Kodack DP, Chung E, Yamashita H, et al. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases [published online ahead of print October 15, 2012]. Proc Natl Acad Sci U S A. 2012;109(45): E3119-3127.
4. Lin NU, Gelman RS, Younger WJ, et al. Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases. J Clin Oncol. 2013; 31(suppl; abstr 513).