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	When Robert A. Weinberg was a boy, he loved dissecting what was complicated and figuring out what made it work.

	When he wasn’t taking apart electric trains, he was studying genealogy, tracing the branches of his family tree.

	But during those years in Pittsburgh, Pennsylvania, Weinberg had no idea where that passion might lead him.

	He attended the Massachusetts Institute of Technology (MIT) because friends of his parents had gone there. He pursued medicine because “in those days, young Jewish boys became doctors” and switched to biology when he made the alarming discovery that “doctors had to stay up all night taking care of patients.”

	“I’m not a person who’s planned out his course in life,” said Weinberg, 68, a renowned oncology researcher whose work has changed the world’s understanding of cancer. “I just stumble from one steppingstone to the next.”

	Through a combination of talent and circumstance, that series of stumbles has coalesced into a long and successful career for Weinberg, a member of the US National Academy of Sciences who was presented with the National Medal of Science by President Bill Clinton in 1997 and named Scientist of the Year by Discover magazine in 1982 .

	Weinberg’s discovery of the first cellular oncogene in mammalian cells, Ras, provided researchers with a deeper understanding of cancer that helped pave the way for the growing tide of targeted cancer therapies. Weinberg and his colleagues made another landmark discovery when they became the first to figure out what makes a normal, dormant gene change into a virulent oncogene. His lab also discovered the tumor suppressor retinoblastoma protein, opening the door to the isolation and study of genes that prevent the onset of cancer.

	In 2000, Weinberg shared his comprehensive insights into what makes cancer cells abnormal by co-writing the seminal paper “Hallmarks of Cancer,” the most cited Cell journal article of all time.

	“I’m driven by trying to figure things out,” Weinberg said. “It’s an unrelenting drive leading to occasional ‘eureka’ moments, with a lot of grunt work in between.”

	Weinberg is director of the Ludwig Center for Molecular Oncology at MIT, where he is also a professor of biology. He joined the staff of his alma mater in the early 1970s, when he became part of its newly formed Center for Cancer Research. Nearly a decade after that, Weinberg became a founding member of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, where his lab remains.

	Although Weinberg says he hasn’t “touched a test tube in 30 years,” he attends scientific meetings nearly every day in his own lab or with other colleagues to discuss results, offer critiques, and suggest additional experiments. To support that work, he wades through a constant “blizzard of e-mails” and edits the manuscripts of the researchers who work in his lab.

	Lately, Weinberg has devoted a lot of time to revising a work of which he’s very proud: his 2007 graduate-level textbook, 

. He gives talks at about 25 scientific meetings each year, and at MIT he spends about 15% of his time teaching half a course in introductory biology for undergraduates, along with half a graduate course in cancer biology.

	In front of the classroom, Weinberg likes to entertain his undergraduates by revealing that he got a “D” in introductory biology, a course he didn’t enjoy when he took it at MIT. And he passes on this wisdom: “Most of the young people in high school have the conviction that biology is all about memorizing facts, when, in fact, it’s a very logical science with a lot of interesting questions that remain unexplored. It’s a very intellectually challenging field.”

	While Weinberg wasn’t excited by his initial coursework during his days as a biology student, he found himself in the right place at the right time.

	“The revolution in microbiology was just erupting,” Weinberg said. “As a junior, I was exposed to the genetic code, which was just being deciphered. All of a sudden it got very interesting, so I became interested in a serious way in the new biology— molecular biology&mdash;[and] in taking apart complicated things into their component parts, just like taking apart old electric motors.”

			With his wife, Amy, has 2 children: Aron, 32, and Leah Rosa, 30. Neither is a scientist.

			Is the son of parents who escaped Nazi Germany in 1938. “It made me realize that one should take very little for granted, that things are much more fragile and vulnerable to change than one imagines.”

			Knew early on that he didn’t want to be a dentist like his father. “My father spent his life looking in people’s mouths, and his father was a horse dealer who spent his life, in turn, looking in the mouths of horses. I didn’t want to be looking into mouths anymore.”

			Was taught as a child that behaving decently, having a sense of humor, and being learned were important, but that making a lot of money was not.

			Shrugs off adversity with a saying of his mother’s: “No matter what you do, it’s wrong in someone’s eyes.”

			Built a cabin in New Hampshire and enjoys gardening there, along with “mucking around the woods in my overalls.”

 as his favorite movie because “it was so mind-blowing when I saw it 30 years ago.”

			Has been the recipient of nearly 60 awards and honors for his work; has participated in 10 scientific committees, panels and symposia, in most cases as chairman; and has been a member of a dozen scientific advisory boards.

			Is “skeptical of those who go into cancer research to save humanity, because without the additional drive of finding it highly interesting, I don’t think one discovers that much. One needs to be motivated, in part, by some kind of burning curiosity.”

			Believes the “funding climate is very discouraging for young people going into basic biomedical research. Lots of funds are being put into multiteam collaborative efforts, which yield far less than the funding of individual labs.”

	Yet at the same time, another revolution was in progress, and it pulled Weinberg away from his studies. In 1965, after a year of graduate school, Weinberg left MIT to teach at Stillman College, a predominantly black institution in Tuscaloosa, Alabama. The city had just been ravaged by a hurricane, and the fight for desegregation was in full swing.

	“I did feel I needed to do something for the world, and it was a time when people with my talents were needed,” said Weinberg. “I was the undergraduate biology department in that college that year. On weekends, I would buy sacks of fl our and rice and beans and carry them out to the tent cities of sharecroppers in Greene County, who’d been evicted from their land because they’d registered to vote.”

	“Everybody was sure I’d stay in Alabama or end up getting buried under a dam, which had happened to some civil rights workers the year before,” Weinberg added. “But much to everyone’s surprise, I came back to MIT in 1966 and finished my PhD work.”

	Weinberg went on to complete 2 postdoctoral fellowships: one with Ernest Winocour, PhD, at the Weizmann Institute of Science in Rehovot, Israel, where Weinberg enjoyed meeting and spending time with relatives; and the other with Renato Dulbecco, MD, at the Salk Institute for Biological Studies, in La Jolla, California, where Weinberg worked with the DNA tumor virus SV40 to study RNA metabolism.

	Weinberg was at the Salk Institute when he received a visit from his future. It came in the form of Salvador Luria, MD, a pioneer molecular biologist who was on staff at MIT.

	“He told me I was going to be part of a new MIT cancer center he was founding,” recalled Weinberg. “He didn’t ask; he just told me. After a couple of days I said ‘OK,’ so I ended up coming back to MIT—not because I’d planned to do so. It just happened.”

	In his first year at the cancer center, Weinberg worked as a research associate to David Baltimore, PhD, who had just discovered reverse transcriptase—a revelation that, 3 years later, would earn him the Nobel Prize. Baltimore shared it with 2 others, including Dulbecco. Intrigued by Baltimore’s work, Weinberg decided to explore retroviruses in his own lab.

	“Around 1977, we became involved in studying viral oncogenes, and that led to us discover, in 1979, the first cellular oncogene in mammalian cells,” Weinberg said. “It was the most important thing that ever happened in my lab.”

	The experiment involved taking genes from cells that had been exposed to a chemical carcinogen and putting those genes into normal cells. The result was that the normal cells became cancerous, proving for the first time that cancer is a genetic disease. The finding led to the discovery of additional oncogenes by other labs, opening the door to the possibility of targeted cancer therapies.

	“It’s not as if somebody else would not have done it a year or two later,” a modest Weinberg said of his finding. “But that was my moment in the sun.”

In recent years, Professor Weinberg has been exploring the role of the epithelialmesenchymal transition (EMT) process in promoting the development of metastatic tumors. Weinberg discussed some of his theories during a June 5 plenary session lecture at the American Society of Clinical Oncology annual meeting, where he was honored with the Science of Oncology Award.

		Here are excerpts from the noted researcher’s presentation, as well as answers to questions that OncLive posed:

			EMT is a complex, multifaceted program involving multiple changes in cell properties.

			EMT allows carcinoma cells to physically disseminate from primary tumors and, in the process, acquire stem cell properties that can initiate new tumors.

			Chemotherapeutic agents typically kill noncancer stem cells preferentially, creating “a dangerous situation because not only have these cells survived the initial onslaught of chemotherapy or radiotherapy but in addition they are capable of repopulating an entire tumor.”

		“We will not succeed if we wipe out only the cancer stem cells, we will not succeed if we wipe out only the nonstem cells.” Weinberg said. “Both populations of cells need to be targeted in order to hope to achieve a durable clinical response given the plasticity and the bidirectional interconversion between these two different cell types.”

 YIn the lab, your m ost recent work has involved investigating how cancer cells spread, causing tumor recurrence. Can you explain more about these efforts?

Now that we have an understanding of how cancer cells can form primary tumors, we want to figure out how cancer kills people through the spread of primary tumors to distant sites in the body. Until recently, it’s been a mystery how cancer cells could acquire multiple powers to generate metastases.

		Over the last five or 10 years, through a number of labs, including mine, we’ve learned that cancer cells do this by activating a dormant embryonic program in which normal cells migrate from one part of an embryo to another. The reactivation of this program, known as EMT, enables cancer cells to acquire a number of traits that, together, allow them to disseminate and spread to distant organ sites.

			Clinical implications: Most currently used chemotherapeutics kill noncancer stem cells (CSCs) preferentially.

			Adapted from Weinberg RA. The EMT and the pathogenesis of high-grade carcinomas. Presented at the American Society of Clinical Oncology Annual Meeting; June 5, 2011.

What role did your lab play in discovering this mechanism?

		Although this was not our idea to begin with, it had never been examined experimentally. We did some of the first direct demonstrations of this as the case, and validated that this was a powerful idea. Two years ago, we reported that the product of forcing a cancer cell through an EMT program is a cancer stem cell that has the power to seed a new tumor. If you put it into a mouse, it can generate an entire tumor.

How will this work change the direction of cancer research?

		This demonstrated that cancer stem cells are more resistant to chemotherapies than nonstem cells, so there are subpopulations of cancer cells in tumors that have greater or lesser sensitivity to being killed by anticancer therapeutics. This knowledge will allow the research community to generate new cancer stem cells that can then be tested for their susceptibility to being treated by existing cancer treatments.

	The achievement didn’t escape the notice of Baltimore, who appointed Weinberg as a lab head when he founded the Whitehead Institute in 1982. It turned out to be a wise decision. During Weinberg’s first year at the Whitehead Institute, he experienced the biggest “aha” moment of his career.

	He and his colleagues converted a normal gene into a cancer-causing bladder carcinoma oncogene, demonstrating for the first time how a healthy, dormant gene can be transformed into a virulent oncogene.

	The cause of the cancer, Weinberg was fascinated to find, “was a point mutation, a single letter or base of DNA among the thousands of bases that, together, constitute a gene.”

	Eight years later, Weinberg shared his comprehensive understanding in “The Hallmarks of Cancer,” which was co-authored by Douglas Hanahan, PhD. The article discussed “6 principles, or hallmarks, that turned out to be a very useful conceptualization that explains much of what makes cancer cells abnormal,” Weinberg said. He and Hanahan updated the article this year, adding information about more recently identified biological mechanisms that contribute to the creation of tumors.

	In addition, Weinberg continues to unravel the mystery of cancer in his lab, where he and colleagues are researching the molecular mechanisms that control carcinoma progression and metastasis. Combined, his projects are all-encompassing— not so different, ironically, from the prospect of all-night patient care that discouraged him from pursuing a medical degree during his days as a student. Still, Weinberg has no intention of slowing his pace.

	“I don’t have time to read a book or to listen to music, which I love doing, so that’s been a real sacrifice. It’s been going on for 40 years, and I can’t get them back,” the scientist said. “Still, I feel blessed. Ninety-five percent of the people in the world don’t enjoy what they’re doing, so my career has been a stroke of good fortune, a gift which I’ve never taken for granted.”

	It’s a career whose legacy, Weinberg hopes, will reach far into the future—in particular, through the work of the talented younger scientists he’s mentored over the years.

	“What I’m most proud of,” he said, “is the people I’ve trained. That kind of satisfaction continues to come back to me, and that’s all I can hope for.”

	Beth Fand Incollingo is a New Jersey-based writer and editor, and owner of the communications firm Texterity, LLC.

Articles

When Robert A. Weinberg was a boy, he loved dissecting what was complicated and figuring out what made it work.

Those Eureka Moments Glisten: A Conversation With Robert A. Weinberg, PhD

		Steven A. Kriegsman, president and chief executive officer of CytRx

	Amid growing cost pressures in the pharmaceutical industry, many small companies are playing an increasingly active role in drug development. One such company is CytRx Corporation, based in Los Angeles, California.

	CytRx, which is traded on the Nasdaq, recently completed several transactions, including the sale of its molecular chaperone technology, which have the potential to generate more than $120 million for its oncology research. The company’s pipeline consists of 3 oncology drugs: INN0-206, under investigation in soft-tissue sarcomas; tamibarotene, under study in a placebo-controlled, double-blind study for non-small cell lung cancer (NSCLC) and a pivotal phase II trial in acute promyelocytic leukemia; and bafetinib, under study in a phase II proof-of-concept trial for relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL) and in clinical trials in advanced prostate cancer and brain cancer. The FDA approved orphan drug status for INNO-206 in July, which carries potential tax credits and extended patent rights.

	Steven A. Kriegsman, a former certified public accountant and healthcare investor, is the president and chief executive officer of CytRx. Daniel Levitt, MD, PhD, chief medical officer, has more than 24 years’ experience managing clinical trials and drug development programs for several major pharmaceutical companies. They discuss CytRx’s research and the challenges of oncology drug development.

		Daniel Levitt, MD, PhD, chief medical officer of CytRx

 The drug INNO-206 is a tumor-targeted conjugate of the commonly prescribed chemotherapy drug doxorubicin, which is used to treat a number of different types of cancer. In the INNO-206 formulation, doxorubicin is chemically linked to a second molecule that, when administered into the body, will bind very specifically to albumin, the major protein in the human circulation system.

	Albumin is known to concentrate in tumors. In this situation, it acts as a carrier for INNO-206. Tumors have been shown to have a very acidic environment. They receive less oxygen and metabolize sugar to lactic acid, which leads to a higher acid content and a lower pH inside the tumor. At a lower pH, the doxorubicin is released from the albumin and from the linker, and then enters the tumor cell where it achieves a much higher concentration than if you administer just the free doxorubicin by itself.

	What would be the advantages of INNO-206?

 You can administer much higher doses of the drug doxorubicin using this linker, which leads to greater activity. You get less toxicity and a lower side-effect profile. Basically, there’s a chance of actually creating a much greater destructive impact at the site of the tumor. This all leads to boosting the activity of the doxorubicin, increasing the tumor’s exposure to the drug by 300 to 400%.

 INNO-206 is really our first platform technology, and what makes it unique is that we have the ability to take that acid-sensitive linker and apply it to other chemotherapeutics.

		The molecular structure of INNO-206, and an illustration of its mechanism of action.

 Tamibarotene is being developed in a pivotal trial for acute promyelocytic leukemia as a third-line drug. And perhaps more excitingly, it has just entered into a placebo-controlled, double-blind phase II trial for NSCLC.

	We believe that its potential to improve overall survival, progressionfree survival, and tumor response for patients with stage IV lung cancer is the real opportunity here, based on very encouraging preliminary results with a far less potent drug in the same class as tamibarotene.

	We’re focused on our 140-patient phase IIB clinical trial that compares adding tamibarotene to a standard chemotherapy regimen versus a placebo added to a standard chemotherapy regimen in patients who have stage IV NSCLC, the most aggressive or late stage of this cancer. And we hope to have some of these results the latter part of next year.

	Is tamibarotene the company’s most promising drug?

 I think that each of our drugs, for their specific indications, has a great deal of promise. Only the data will tell the story at the end. But, certainly, we feel tamibarotene is very promising based upon preliminary results with a drug in the same class as tamibarotene, called ATRA [alltrans retinoic acid], that is far less potent than tamibarotene. But, as I mentioned previously, we also feel that INNO-206, because of its ability to target tumors, the ability to administer much higher doses of the drug with fewer side effects, also has a great deal of promise.

 This is a drug that targets a number of enzymes, called kinases, that mediate cell growth, cell differentiation, etc, and are either overexpressed or mutated in a variety of different tumors. Bafetinib specifically inhibits enzymes called Lyn and Fyn kinases, which are expressed at very high levels in tumors such as B-CLL and glioblastoma multiforme.

	CytRx recently reported preliminary results from its ENABLE phase II trial demonstrating that bafetinib was clinically active in patients with relapsed B-CLL who failed several other cancer treatments. Based on this indication of clinical activity and the low incidence of adverse events, additional patients enrolled in the ENABLE phase II trial will receive bafetinib as a single agent at a higher dose. The results validate CytRx’s strategy to rapidly and cost effectively conduct proof-of-concept trials in patients with advanced-stage cancers prior to moving into larger trials.

		INNO-206 linker binds to albumin, which preferentially collects in the tumor.

	How is CytRx generating the money to develop these drugs?

 Our monetization strategy to date has been very proactive in taking our legacy assets and monetizing them. We actually had a cash profit last year as a result of that strategy, even as we increased our focus on oncology development. We reported over $30 million of cash and cash equivalents at the end of March. Though we had opportunities to raise additional financing, because of our aggressive asset monetization strategy, we were able to fund our operations without diluting out stockholders. We keep a very tight handle on the overhead, and are able to manage our clinical development with 14 full-time employees.

	Does CytRx plan to bring these drugs to market itself?

 The view of our Board of Directors to date has been: Take everything to market that you can, build a sales force and a marketing team, and sell wherever you can worldwide.

	But with INNO-206, it might be hard for us to do justice to that significant of a platform without possibly leveraging the resources of a partner due to the costs involved. It’s too big for a company our size or even a company probably with an extra $100 million in cash. That’s something where in order to do parallel trials in many, many different chemos and many different indications, you need enormously deep pockets, which we don’t have and will not have for quite a while. So that’s the most likely, I think, partnerable drug.

	As far as tamibarotene, if that goes well, we have the rights to Europe and North America. For that drug candidate, we would take it to market and have a sales force. I think it would depend upon how much money we had and where we stood.

	Obviously, the more you partner, the less you have for yourself. But on the platform technology, it would be better to structure a favorable transaction and get cash up front to fund additional development projects.

	What advantages do you feel your company has?

 I think it’s rare among publicly traded oncology companies and biotechs that are smaller in size that you have a management team that has had a hand in 6 oncology drugs coming to market. Dan Levitt’s been involved with 5, and Scott Geyer, our senior vice president of manufacturing, had a hand in the development and FDA approval of Nexavar.

	What challenges do you see going forward?

 I think the challenge is always the unknown. You just don’t know what’s going to happen until the race to get a drug to market has ended, and either you’re successful and you get the FDA to approve your compound and you bring it to market or you’re not. That’s the ultimate challenge—to keep a company alive financially and obtain the fuel in the engine to drive to the finish line. It’s like in the Indianapolis 500. If your team runs out of gas on lap 499, somebody is going to be pretty upset that you couldn’t cross the finish line. In our business, the gas is the money.

 I think that’s true. You’re dealing with 2 issues, time and money. It takes time to develop a drug to the market. You’re looking at an average somewhere between 7 or 8 years for most drugs. That’s a long road, and to be able to maintain development financially is the challenge, but a challenge we are prepared to meet.

Amid growing cost pressures in the pharmaceutical industry, many small companies are playing an increasingly active role in drug development.

Building Blocks of a Biotech: CytRx Executives Talk About 3 Agents for Multiple Tumors

	In the 2 decades since the discovery of the JAK-STAT signaling pathway, intense research has resulted in its becoming one of the best-understood signal transduction cascades.

	However, it is only in recent years that cancer researchers have begun to enjoy the fruits of this research, and even now JAK inhibitors are in their infancy compared with other targeted therapies. The development of these agents may offer new hope, particularly for treatment-resistant forms of chronic leukemia.

	Found in slime molds and humans alike, JAK-STAT signaling is relatively simple, as signal transduction pathways go. There are 3 principal components: a receptor, a member of the Janus kinase (JAK) family, and a member of the signal transducer and activator of transcription (STAT) family. This pathway handles incoming signals from a number of different membrane receptors, most importantly the cytokine receptors.

	Named originally for the 2-faced god of Roman mythology, JAK is involved in signal transduction in both normal cells and disease states. It was often referred to as “Just Another Kinase” because its role initially was not fully defined. We now know that there are 4 members of the JAK family of nonreceptor tyrosine kinases: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).

	Once activated, the JAKs phosphorylate their major target, the STATs, of which there are 7. The STATs are transcription factors that normally lie dormant in the cytoplasm, but when phosphorylated they move into the nucleus where they bind to specific DNA sequences and drive or inhibit the suppression of target genes.

	This relatively simple mechanism offers a means of directly translating incoming signals from outside the cell into cellular responses much more quickly than other signal transduction pathways, with each particular type of receptor-JAK-STAT combination driving a specific response. What is more complex and less well-understood is the considerable crosstalk between JAK-STAT and other signaling pathways.

	Important in Hematopoiesis, Blood Cancer

	JAK activation stimulates numerous cellular processes, including proliferation, differentiation, migration, and apoptosis. It plays a particularly important role in the formation and development of blood cells (hematopoiesis) and in proper immune function. Aberrant JAK-STAT signaling is therefore implicated in the development of blood cancer.

	It was not until 2005 that mutations in the 

 gene were directly linked to the development of cancer, with the identification of the V617F point mutation in 

. This defect has subsequently been shown to be important in the development of myeloproliferative neoplasms (MPNs), characterized by the overproduction of blood cells.

	The MPNs can be further characterized by the presence or absence of the Philadelphia chromosome, a chromosomal abnormality in which parts of chromosomes 9 and 22 break off and exchange places. The result is that 2 genes, breakpoint cluster region (

) and Abelson tyrosine kinase (ABL), form the oncogenic 

	The treatment of MPNs initially showed promise with the development of targeted therapies such as gefitinib (Iressa, AstraZeneca) and imatinib (Gleevec, Novartis). However, patients with the 3 Philadelphia chromosome-negative forms of MPN, namely myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET), were resistant to these treatments. The 

 V617F mutation has been detected in >80% of PV cases, from about 40% to 70% of ET cases, and from about 40% to 60% of MF cases.

	The main source of morbidity and mortality in patients with MPN is the development of thrombotic and hemorrhagic events and the risk of transformation to acute myeloid leukemia (AML), which has a particularly poor prognosis. With the exception of stem cell transplants, there are currently no curative treatments for these disorders.

	Thus, the discovery that JAK-STAT signaling is frequently perturbed in these forms of MPN was an exciting and important breakthrough. In the 6 years since, a number of biotech companies have streamlined JAK2 inhibitor development, and these compounds have already demonstrated dramatic improvements in quality of life and reduction of spleen size in a significant proportion of patients participating in clinical trials.

	Furthest along in development among the JAK inhibitors is ruxolitinib (INCB18424, Incyte Corporation), an inhibitor that targets both JAK1 and JAK2. The FDA has granted orphan drug status for the use of ruxolitinib, and Incyte has submitted a new drug application for use of the drug in MF based on recent trial results reported at the 2011 American Society of Clinical Oncology annual meeting in Chicago. (

Ruxolitinib Results Promising in 2 Myelofibrosis Studies

	Hot on its heels are a number of other JAK2 inhibitors, including YM BioSciences Inc’s CYT387, for which interim updated safety and efficacy results also were presented at ASCO.

	Other JAK2 inhibitors in development include lestaurtinib (CEP-701, Cephalon), though its development may be hampered by the fact that other agents have higher activity and better safety profi les. TG101348 (Sanofi ), XL019 (Exelixis, Inc), SB1518 (S*BIO Pte Ltd), and AZD1480 (AstraZeneca), are all also currently undergoing phase I and II clinical testing, though high dropout rates have recently halted the development of XL019. INCB028050, INCB16562 (both from Incyte), NVPBSK805 (Novartis), and R723 (Miyazaki University) are undergoing preclinical evaluation.

	Researchers expect that JAK2 inhibitors will become the new standard of care for patients with primary MF, and post-ET and post-PV MF in the near future.

	However, although these molecules have shown significant clinical success, the effects have been more palliative than curative. The drugs do not demonstrate a complete response in JAK2 V617F-positive patients, and relapses occur upon cessation of inhibitor therapy.

	Experts now widely believe that JAK inhibitors will make much more of an impact in combination with other targeted therapies. Potential candidates include inhibitors of histone posttranslational modifi cation (ie, histone deacetylase [HDAC] inhibitors) and immunomodulatory drugs. Indeed, JAK2 inhibitors have exhibited synergy with HDAC inhibitors during in vitro studies.

	The therapeutic role of JAK2 inhibitors is not limited to MPNs. In the future, they may also play a role in the treatment of other hematopoietic malignancies and solid tumors with aberrant activation of the JAK-STAT pathway, such as Philadelphia chromosome-negative leukemias, acute lymphoblastic leukemia, AML, multiple myeloma, and non-Hodgkin lymphoma.

	Recent research also has shown that a cytokine- JAK-STAT5 signaling combination is important in the development of breast tissue and that aberrant JAK-STAT signaling may play a role in breast cancer development. These findings highlight the burgeoning understanding of the role of the JAKSTAT pathway in a variety of solid tumors, which may prove to be the focus of future clinical research.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.

			Incyte Corporation. Janus-associated kinase (JAK) pathway: dysregulation and therapeutic opportunities. Incyte Corporation Website. 

			Incyte Corporation. Pathogenic mechanisms. JAK pathway. MPN Connect Website. 

			Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. 

			Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. 

			Pardanani A, Vannucchi AM, Passamonti F, Cervantes F, Barbui T, Tefferi A. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations [published online ahead of print November 16, 2010]. 

			Pardanani A, Tefferi A. Targeting myeloproliferative neoplasms with JAK inhibitors. 

			Quintás-Cardama A, Verstovsek S. New JAK2 inhibitors for myeloproliferative neoplasms. 

 2011; 20(7):961-972. doi: 10.1517/13543784.2011.579560.

			Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. 

			Weinberg I. Janus kinase 2 (JAK2). Angiolist.com Website. 

. Published April 27, 2010. Accessed June 20, 2011.

Intense research has resulted in JAK-STAT becoming one of the best-understood signal transduction cascades.

JAK-STAT Signaling Has Many Faces: Inhibitors Offer Hope in Rare Blood Cancers

	Srdan Verstovsek, MD, PhD, is a medical oncologist and associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston. He is the leader of the myeloproliferative disorders program, with research interests in understanding their biology, and developing and testing novel therapies. He has been involved in the clinical testing of Incyte’s ruxolitinib.

	 What role does JAK signaling play in normal physiology?

	JAKs are critical elements in the signaling of a number of cytokines (eg, interleukins and interferons) and growth factors (eg, erythropoietin and thrombopoietin) that are involved in normal bone marrow and immune cell functions. They stimulate JAK signaling upon binding to their respective cell surface receptors, ultimately leading to a number of cellular functions, including activation and proliferation. JAKs use transcription factors known as STATs to propagate the signals, and this pathway is therefore often referred to as the JAK-STAT pathway.

	 How important is JAK signaling in cancer?

	A number of lines of evidence implicated unchecked activation of the JAK-STAT pathway in the development of hematological malignancies, including myeloid and lymphoid leukemias. The earliest hint came from evidence that transformation of pre-B cells by v-abl resulted in persistent phosphorylation and activation of STAT.

	Then, in 1997, a chromosomal translocation involving 

, a gene encoding a member of the ETS transcription factor family, was associated with several types of leukemia. Most recently, an activating mutation in 

, that results in a single amino acid substitution was discovered in Philadelphia chromosome-negative myeloproliferative neoplasms.

	Although not widely prevalent in other types of blood cancers, this led to immense interest in this pathway. We are also beginning to appreciate the role of JAK-STAT signaling in solid tumors including breast cancer, pancreatic cancer, and non-small cell lung cancer.

	 What is the future of JAK signaling in cancer research?

	With the availability of selective, potent, and orally available JAK inhibitors with excellent tolerability profi le, I expect that there will be a great deal of interest in testing these agents in various cancers that are associated with dysregulated JAK-STAT signaling.

	In addition, JAK inhibitors could be combined with other agents based on the mechanistic rationale that STAT signaling is potentially involved in resistance to chemotherapeutic agents and other tyrosine kinase inhibitors.

Srdan Verstovsek, MD, PhD, is a medical oncologist and associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston.

3 Questions for Srdan Verstovsek, MD, PhD

	Every decade during the past 50 years, treatment for multiple myeloma (MM) has taken a leap forward. Now, novel therapies developed at a relatively rapid pace are poised to deliver a new era of advances that promise to signifi cantly prolong the lives of many patients.

	“It’s a new world in multiple myeloma,” leading researcher Kenneth C. Anderson, MD, said in an interview with OncLive. “We’ve had novel therapies that have already transformed the natural history of the disease, but due to advances in genomics on the one hand and novel targeted therapies on the other, the best is yet to come.”

	Anderson, a professor at Harvard Medical School and director of the LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston, Massachusetts, was recognized for his contributions to MM research at the 2011 American Society of Clinical Oncology (ASCO) annual meeting in Chicago on June 4. He received the society’s highest honor, the David A. Karnofsky Memorial Award.

	“What’s really changed things in our disease is the advent of novel therapies, starting with thalidomide in the late 1990s, which have quite literally transformed the way we think about and treat multiple myeloma,” Anderson said in his ASCO speech.

	“We have a new treatment paradigm based on targeting the tumor in the microenvironment, and it has really, for many patients, made myeloma a chronic illness already,” he said in an interview.

		Developments in Multiple Myeloma Research

		Adapted from Anderson KC. Bench to bedside translation of targeted therapies in multiple myeloma. Presented at 2011 American Society of Clinical Oncology Annual Meeting; June 4, 2011; Chicago, Il.

	Anderson said the median survival for MM patients is now 7 years, more than double the rates of the early 1960s, when chemotherapeutic melphalan was introduced.

	In May, Anderson joined in unveiling results of a large, phase III trial demonstrating the benefi ts of lenalidomide at the 13th International Myeloma Workshop in Paris, France. The drug, administered orally, nearly doubled the median time-to-progression to 43.6 months for patients with stage I/III MM who took the capsules continuously as maintenance therapy after autologous stem cell transplant, versus 21.5 months for the placebo group.

	Questions linger about whether patients face the risk of developing second cancers. Anderson has said the incidence does not appear higher than the rate normally associated with aging, and that the benefi ts outweigh the risk.

	Now that novel therapies are producing such notable results, researchers are focusing on combinations that will move patients with MM away from stem cell transplants as a fi rst option for treatment, Brian G.M. Durie, MD, chairman of the International Myeloma Foundation and vice-chair of the Myeloma Committee of the Southwest Oncology Group, said in an interview.

	“These new types of drugs have a much more powerful impact on myeloma and are well tolerated and are not traditional chemotherapy,” he said. “… It’s a big, big change.”

	Anderson said in his ASCO presentation that promising studies are underway, particularly trials combining bortezomib and lenalidomide. He said the drugs kill myeloma cells by distinct mechanisms and can trigger dual apoptotic signaling. When used upfront in phase I/II trials, the combination demonstrated a nearly 100% response rate, including a >50% complete or near-complete response, Anderson said.

		We are trying to develop cocktails of therapies that would be used in the overwhelming majority of patients and will achieve extent and frequency of responses. At the same time, few, if any, patients are being cured, and so we need to understand better both at the time of diagnosis, but especially at the time that myeloma comes back or relapses, what are the characteristics of that myeloma so that we can effectively target in the early, newly diagnosed patients to prevent the drug resistance from developing.

		I think on the one hand combinations of multiple drugs, probably 4 or even 5 drugs based on science, will become quickly in order to not only get responses in everybody but to get hopefully complete or near-complete responses in everybody.

		We’ll have further research on the maintenance [therapies]. With lenalidomide, it’s a clear major advance, but do we need to have more than one drug for maintenance, or are there other agents that can also be very effective?

		Then on the biomarker, what I like to call personalized medicine front, there’s a lot of research using genomics tests to better segment patients with myeloma, better understand who responds or who doesn’t, and why.

		I think there are really two ways forward right now. We have these novel agents that have given us important clues about types of treatment that can work better in myeloma. The first thing is that we discovered that these drugs that work as IMiDs [immunomodulatory drugs] and as proteasome inhibitors can really make an important difference. So finally we had targets. We realized that if we tackle these targets, it is a good place to start in shutting down myeloma. And so the one way forward is to refine those targets, and then maybe combine those targets with some other targets.

		The second approach is to keep looking for a cure. In other words, we want an approach that can just really wipe out a myeloma, and could that come from some combination of those new drugs? I think everyone is expecting that we need some slightly new idea that would finally come up with that cure.

Every decade during the past 50 years, treatment for multiple myeloma has taken a leap forward.

Novel Therapies Usher in New Era

	Ruxolitinib, an investigational JAK inhibitor, demonstrated significant benefits for patients with myelofibrosis in 2 studies presented during the American Society of Clinical Oncology annual meeting in Chicago, Illinois, June 3-7.

	Before the congress ended, Incyte Corporation submitted data from the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) trials to the FDA as part of a new drug application.

	COMFORT-II compared ruxolitinib with the best available therapy for the bone marrow disorder, and showed that ruxolitinib significantly reduced spleen size and volume (

	Ruxolitinib also reduced symptom burden and improved quality of life (QOL), said one of the study’s authors, Alessandro Maria Vannucchi, MD, of the University of Florence in Italy, who presented the results.

	COMFORT-II was an open-label trial that enrolled 219 patients with intermediate-2 or high-risk primary myelofibrosis, postpolycythemia vera myelofibrosis, or postessential thrombocythemia myelofi brosis. Patients were randomized in a 2:1 ratio to ruxolitinib 15 or 20 mg twice daily or to best available therapy and were treated for 48 weeks.

		FIGURE. Change in Select EORTC QLQ-C30 Scores for Patients With Myelofi brosis at Week 48 Compared With Baseline in COMFORT II*

Improvements were seen by week 8 and continued through week 48

		*EORTC QLQ-30 = European Organisation for Research and Treatment of Cancer Quality of Life Version 3.0 questionnaire †Ruxolitinib, n = 68

		Adapted from Harrison CN, Kiladjian J, Al-Ali H, et al. Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofi brosis (PMF), post-polycythemia vera-myelofi brosis (PPV-MF) or post-essential thrombocythemiamyelofi brosis (PET-MF). 

	In the control arm, 67% of patients were treated with at least 1 medication; 47% of those treated received hydroxyurea and 16% were given glucocorticoids.

	The percentage of patients who met the primary endpoint (ie, at least 35% shrinkage in spleen volume at week 48) was 28.5% for ruxolitinib versus 0% for best available therapy (

 <.0001). Median time to response was 12 weeks.

	A marked improvement in QOL accompanied the reduction in spleen volume 

	At baseline, about 60% of patients had anemia, and grade 3/4 anemia was reported in 42% of the experimental arm versus 31% in the control group. No survival benefit has emerged but follow-up was short.

	In COMFORT-I, 41.9% of the ruxolitinibtreated patients versus 0.7% of the placebo group achieved the primary endpoint (ie, at least 35% shrinkage in spleen volume at week 48, P <.0001) at median follow-up of 32 weeks. Symptom burden was also signifi cantly improved (P <.0001) with ruxolitinib versus placebo. More thrombocytopenia and anemia were observed in the ruxolitinib arm.

Ruxolitinib, an investigational JAK inhibitor, demonstrated significant benefits for patients with myelofibrosis.

 It is clearly common practice among all clinical oncologists to ask themselves the following question at the completion of each annual meeting of the American Society of Clinical Oncology (ASCO): “Which studies should influence how I manage my patients and what criteria should I use to make these decisions?”

	Before I present my perspective on these important issues, I want to emphasize both the increasing urgency and complexity of these questions. The data are no longer solely in the domain of the treating oncologist, with both company press releases and extensive information on the Internet frequently resulting in inquiries from patients and their families soon after such reports are available to the public.

	Few would likely argue with the conclusion that it is reasonable to consider for routine clinical use a “novel regimen” reported at ASCO that contained commercially available antineoplastic agents or combined such drugs with other standard modalities (eg, surgery, external beam radiation), and that revealed a statistically significant impact on overall survival in a particular clinical setting.

	Of course, one might hear a few purists declare that the true “gold standard” in this arena is the actual publication of the data from such a trial in the peer-reviewed medical literature. But unless there are claims, either in meeting-based discussions of the abstract or through other sources, that there is a serious concern with what has been stated in the abstract/presentation, it is difficult to argue that patients in the specific clinical setting should be denied the potential benefits of the new strategy while the publication process runs its natural—and often protracted&mdash;course.

	Phase III randomized trial data reported to be “positive” but not for an overall survival endpoint may also form the basis for a change in practice, but in such circumstances additional issues require careful consideration. For example, a documented improvement in progression-free survival or time to progression of cancer-related symptoms may be highly clinically relevant, but one must inquire whether excessive toxicity of the treatment regimen negates any benefit resulting from delay in disease progression.

	Similarly, claimed “statistically significant” results of randomized phase II trials may be quite impressive, but in this setting one might be concerned with the issue of a limited sample size.

Vice President of Patient Oncology Services and National Director for Medical Oncology

		Cancer Treatment Centers of America, Eastern Regional Medical Center

	Nothing in these statements should be taken as implying that the reported “positive” results of randomized trials that fall short of documenting an improvement in overall survival should be ignored, but only that additional questions may need to be asked and answered to the satisfaction of the treating physician.

	Results of nonrandomized phase II studies, and the increasingly common scenario of phase I trials reporting a favorable therapeutic outcome, represent the most difficult reports to define from the perspective of their impact on future noninvestigative disease management. Many such studies are actually modest variations of currently accepted practice and often represent important improvements in a regimen’s therapeutic index, and there will surely be abstracts that appropriately challenge existing management paradigms.

	Here one might argue that the publication of a peer-reviewed paper is particularly relevant since the reviewers of the manuscript hopefully will have specific expertise in the subject and will be able to appropriately scrutinize and validate what has been claimed in the trial’s results. However, as every clinical oncologist knows very well, optimal management of an individual cancer patient is far more complex than that suggested by any published “evidence-based guidelines,” and the delivery of high-quality care requires considerable clinical judgment, as well as frequent and thorough discussion with the patient.

	Finally, it is reasonable to argue that the unquestionable ongoing and truly spectacular revolution in our understanding of the biology of human cancers and the specific impact of knowledge of molecular abnormalities in particular cancers, as well as subsets of these conditions, have rather radically and surely permanently changed the playing field regarding the interpretation of clinical studies.

	For example, how might one interpret the results of a very small clinical trial involving only 4 to 8 research subjects with a rare/uncommon molecular abnormality that revealed an interesting/very surprising level of biological/clinical activity for a currently commercially available antineoplastic agent known (or perhaps more appropriately stated “believed”) to target this specific pathway in another tumor type? While there is no easy answer to this provocative question, it is quite reasonable to predict such reports of small, single institutional prospective or retrospective studies will be far more common in the future.

Which studies should influence how I manage my patients and what criteria should I use to make these decisions?

July 2011 | Oncology Live®

Those Eureka Moments Glisten: A Conversation With Robert A. Weinberg, PhD

Building Blocks of a Biotech: CytRx Executives Talk About 3 Agents for Multiple Tumors

JAK-STAT Signaling Has Many Faces: Inhibitors Offer Hope in Rare Blood Cancers

3 Questions for Srdan Verstovsek, MD, PhD

Novel Therapies Usher in New Era

Ruxolitinib Results Promising in 2 Myelofibrosis Studies

Looking Before Leaping: When to Change Practice Based on ASCO Results

Interim Safety Data Compared in Ixabepilone TITAN Trial

Game-Changers: 11 Key Abstracts in ASCO Lineup

5 Abstracts Offer Snapshot of Immunology Research

Aiming for Immunity: New Therapies in Sights