SINGAPORE, Jan. 6 (Xinhua) — A team of Singaporean scientists have identified a gene responsible for lung cancer, the Agency for Science, Technology and Research said on Friday.

A small number of cells, known as cancer stem cells or tumor- initiating cells (TIC), are responsible for the promotion of tumor growth. The team of scientists found a marker, known as CD166, to identify these cells, it said.

The team, led by Bing Lim, associate director of cancer stem cell biology at the Genome Institute of Singapore, and Elaine Lim, medical oncologist affiliated with Tan Tock Seng Hospital and National Cancer Center Singapore, did more genomic study of the TICs, and discovered several genes that were important for the growth of cancer cells.

The scientists discovered that in abnormal instances when the level of a metabolic enzyme known as glycine decarboxylase rises significantly, it causes changes in the behavior of the cell, making it cancerous.

The glycine decarboxylase is a normal occurring enzyme in cells, present in small quantities.

The finding is reported in the online advance issue of Cell on Jan. 5 and is believed to be a huge step towards finding a cure for the disease.

The breakthrough has been described as a “potential Achilles’ heel” by lead research Professor Alan Clarke.

It comes from the work at the Cancer Research UK Centre in Cardiff into how genes and proteins are involved in the formation of cancer.

Prof Clarke said: “The interesting thing about cancer is that one of its primary features is to turn off a number of defensive mechanisms. As the cancer develops, these defensive mechanisms are got around, usually because the genes are switched off or deactivated.”

But deactivating DNMT1 also had a significant effect on other bodily functions, meaning it would not make a good target for cancer therapies.

MBD2 belongs to a family of proteins which turn off other genes and research carried out in Cardiff has found that deactivating it prevents colon tumours from developing.

“It’s fantastic and does it with virtually 100% efficiency,” Prof Clarke said. “And, taking out MBD2 isn’t that damaging to other tissues and systems – it appears to be tolerated reasonably well.

“Therefore, if we were to have a therapy targeting MBD2, any off-target effects would be limited.”

The research team has been examining the impact of MBD2 by creating mice which lack the gene. But many questions remain unanswered.

Prof Clarke said: “We have to show that if you don’t have MBD2 then the likelihood of getting a tumour is much reduced. And we don’t know if you take out MBD2 from a tumour whether it will disappear.

“We’ve been trying to develop a drug that specifically targets MBD2 but, unfortunately, attempts have not been successful because it’s a very difficult protein.

“We think that MBD2 deficiency suppresses tumorigenesis by failing to turn off a number of genes – some these will be important. We’re trying to delve down and find out which of the genes it regulates are important.

“We have a potential Achilles’ heel here to stop tumours forming and we’re also trying to find a drug target.

“We can imagine that this will be useful for patients who have had a tumour and have had therapy but who have a chance of relapsing. But we’re also testing the notion that regulating MBD2 will cause tumours to regress.”

Prof Clarke added: “The remarkable thing about the way we treat cancer is that we’re stuck with pretty much ancient technology.

“We mostly use poisons but although we have made progress with virtually all forms of cancer in terms of improving treatment, if we are going to make a huge step change it will have to come from a better understanding of the mechanisms that lead to cancer.

“That will come from a molecular understanding of cancer – if we really understand the molecular basis we can create drugs that make a big difference rather than small, incremental differences.”

Cancer, you have a problem

RON DEPINHO is a man on a mission. Oddly, though, he does not yet know exactly what that mission is. Dr DePinho is the new president of the MD Anderson Cancer Centre in Houston, Texas. (He took over in September, having previously headed the Belfer Institute, part of Harvard’s Dana-Farber Cancer Institute.) Mindful of his adopted city’s most famous scientific role, as home to Mission Control for the Apollo project, he says his own mission is akin to a moon shot. He aims to cure not one but five varieties of cancer. What he has not yet decided is: which five?

That it is possible to talk of curing even one sort of cancer is largely thanks to an outfit called the International Cancer Genome Consortium. Researchers belonging to this group, which involves 39 projects in four continents, are using high-throughput DNA-sequencing to examine 50 sorts of tumour. They are comparing the mutations in many examples of each type, to find which are common to a type (and thus, presumably, causative) and which are mere accidents. (The DNA-repair apparatus in malignant cells often goes wrong, so such accidents are common.)

The consortium’s work is progressing fast, and preliminary results for many tumours are already in. But such knowledge is useless unless it can be translated into treatment. That is where Dr DePinho comes in—for his career has taken him into the boardroom as well as the clinic. He is a serial entrepreneur: he helped found Aveo Pharmaceuticals, which is developing a drug to block the growth of blood vessels in tumours, Metamark Genetics, which works on diagnosing cancers, and Karyopharm Therapeutics, which is trying to regulate the passage of molecules into and out of the cell nucleus, and thus control the nucleus’s activities. His aim in coming to MD Anderson, he says, is to “industrialise” other aspects of biological research in the way that genetics has been pushed forward by high-throughput sequencing.

That will cost billions of dollars. Fortunately, the state of Texas—no pushover when it comes to spending taxpayers’ cash—is creating a $3 billion cancer-research fund to help pay for it. Local philanthropists, including T. Boone Pickens and Ross Perot, are chipping in, too. Their model is the original Human Genome Project, during which the cost of sequencing a single genetic “letter” (a DNA base pair) fell from $10 in 1991 to ten cents in 2001—and is now 3,000 base pairs a cent. They hope their dollars will encourage people working with what are now, essentially, craft technologies to think about how they might industrialise them.

Several techniques look ripe for such industrialisation. Dr DePinho sets great store, for example, by the use of genetically modified mice (he calls them “little patients”) in which mutations found in human cancers can be replicated precisely, but one at a time, to discover the shape of each piece of the jigsaw. If this process can be scaled up it will, as he puts it, allow cancer’s genetic generals to be distinguished from the foot soldiers.

Another field that has great potential is imaging technology—in particular, a combination of positron-emission tomography (which uses radioactive sugar to measure how metabolically active tissue is) and computerised tomography (which uses X-rays to map the body’s internal anatomy). Together these can show whether a treatment is reducing a cancer’s energy consumption, and thus its metabolism. This gives a good indication of how well that treatment is working.

A family business

Dr DePinho himself will have more duties at MD Anderson than just dealing with the five chosen tumours. The donkey work of creating the Institute for Applied Cancer Science, as the new mission control is to be known, will be done by Lynda Chin. Dr Chin, too, worked at the Belfer Institute. She is part of the International Scientific Steering Committee of the cancer-genome project. And she is also Dr DePinho’s wife. Dr Chin will be assisted by some 55 other scientists from the Belfer, who are making the journey to Texas with her and her husband. That sort of team poaching is common in investment banking but rarer in academic research. Dr DePinho refers to it, jokingly, as metastasis, since a clone of his primary creation will be taking root elsewhere in the country.

As to which five cancers to attack, that decision will be made by the middle of 2012. A crucial consideration will be how likely it looks that research into the tumour in question could get rapidly to the “proof of concept” stage—the point at which it could be taken forward by a business that relied on commercial sources of capital, rather than on the sorts of grants that usually propel academic research. At that moment a new firm might be spun out of the institute, or a deal might be done with an established pharmaceutical firm, to try to get a new drug developed.

In recent years many big drug companies have gutted their research departments. This is partly because those departments have failed to come up with new “blockbuster” drugs of the sort that created Big Pharma in the first place, and partly because the big firms’ bosses had hoped that smaller biotechnology companies, of the sort Dr DePinho has helped set up, would do the hard work of drug discovery instead, and then let themselves be bought by the big firms.

Unfortunately, it hasn’t quite worked out like that. The output of the biotech firms has been a trickle, rather than a torrent. They have been one of the worst-performing parts of the private-equity market since 2007, according to Dr DePinho. He hopes to change that—and in the matter of new anti-cancer drugs, the science is looking auspicious. For example, a drug called vemurafenib, which was approved for use in America in August 2011, gives months of extra life to people with metastasising melanoma, one of the deadliest cancers. Vemurafenib is so powerful that some people call it a “Lazarus” drug, after the chap Jesus is said to have raised from the dead.

Crucially for Dr DePinho’s project, the development of vemurafenib was stimulated by the identification of a mutated gene often present in melanomas. He and others like him hope that the cancer-genome consortium will throw up dozens of similar genes, and that they, too, will prove tractable targets for drug development.

Of course, if Dr DePinho had a penny for every time a “cure for cancer” headline proved premature, he wouldn’t need munificent donors. But if his bets on the science and on adopting business methods pay off, the drug industry and millions of patients will benefit. That would be one benign sort of metastasis.

By Susan Todd/The Star-Ledger

Noah Murray/The Star-LedgerEstela Jacinto, an associate professor at Robert Wood Johnson Medical School, is carrying out reseach on how cells grow and multiply with the hopes of finding new ways to treat cancer.

This feature is part of “I Am New Jersey,” a Star-Ledger series profiling some of the people who make the Garden State special.

When Estela Jacinto, an associate professor at Robert Wood Johnson Medical School, lectures to her students on the biology of disease, she talks about the complexities involved in cell growth, how chromosomes may develop mysterious kinks and proteins can sometimes cause cells to go haywire. The damage that sets a disease in motion, Jacinto knows, can be caused by so many things — a flash of radiation, an exposure to chemicals, a bout with a virus.

The day after giving one of those familiar lectures last month, Jacinto’s 10-year-old daughter was diagnosed with acute lymphocytic leukemia, and the mother of two found herself tormented by the same questions she has discussed so often as a scientist.

“I tried to think how could I have damaged her genome,” Jacinto says, her voice growing softer. “I know as a kid she had a flu a couple of times, but was that enough to cause leukemia? It’s mind-boggling when you think about all of the things that can go wrong.”

Jacinto, a native of the Philippines with dark eyes and an easy smile, has spent more than a decade studying how normal cells grow and what causes the process to go wrong and allows cancer cells to proliferate.

Much of her research has focused around the activities of the TOR protein, which plays an important role in regulating cell growth. (The protein is the target of the immunosuppressant drug rapamycin resulting in its acronym of a name. When it appears as mTOR, it refers to mammalian cells.)

Jacinto’s efforts in the laboratory resulted in the discovery of a set of protein complexes created by mTOR. By focusing on mTORC2, the more mysterious of the two protein complexes, Jacinto has unlocked new understanding about its function, its relation to nutrients and identified another possible target for attacking a variety of cancers.

“It is still early and there is still a lot of work to be done,” said Jianjie Ma, who has worked over Jacinto for the past two years as her department chair, “but her work has great potential.”

In the field of drug development, some of the newest medicines are being created to inhibit the spread of disease by targeting specific proteins involved in cell growth and survival.

There are high hopes that Jacinto’s research will identify more new targets for treating cancer and other diseases. Earlier this year, she won some recognition — and money — to bolster those efforts. Stand up to Cancer, a group that combines the celebrity of Hollywood and the clout of top-notch scientists to raise money and fund innovative research, chose Jacinto from more than 100 other researchers to receive a $750,000 grant to help pay for her work.

Beyond the giant pharmaceutical companies that make billions selling new medicines, there are academic research laboratories around the world where scientists like Jacinto carry out meticulous experiments, de-assembling proteins and cells in an effort to better understand why the biological process sometimes goes awry, triggering bad cells — and disease.

The research done in these tight, brightly lit spaces scattered with laptops and glass instruments may lead to new insights about the biology of a disease or they may produce break-through medicines. When the research shows enough promise, it might be purchased by a large company or spun off to form the heart of a small, new drug-making firm. The goal is to move it into the clinical setting where it can be studied further and developed into a new treatment.

Terri Kinzy, a senior associate dean for research at Robert Wood Johnson Medical School, helped to recruit Jacinto for a professorship in the school’s department of physiology and biophysics nearly 12 years ago. “I think she really is that person who wants to take her research and translate it into the clinic,” Kinzy says. “She really wants to increase the impact of her work.

“It’s a big challenge,” Kinzy says, “and she likes challenges.”

Jacinto’s passion for her work is well-known among her colleagues. She is described as a collaborator and a mentor, who attracts some of the brightest, hardest-working graduate students to her laboratory.

Ma, who has chaired the department for the past two years, says he has, sometimes, come into the laboratory on weekends to find Jacinto writing a paper or working with a student. “For someone already established,” he says, “she doesn’t have to work that hard.”

Even so, most researchers attribute their successes to a combination of persistence and luck. Ma says Jacinto is someone who has proven she has both.

In some ways, it was an element of serendipity that put Jacinto on the path to becoming a cancer researcher.

“A lot of scientists, when you ask them, say it was their childhood dream to be a scientist. That wasn’t me,” Jacinto says. “I didn’t really know what I wanted to do when I grew up, but I liked science and I said, this is close enough to medicine, I’ll do research.”

Jacinto flirted with the idea of med school when her family immigrated to San Francisco from the Philippines in 1986. Fresh out of the University of the Philippines with a degree in zoology, she applied to both medical schools and graduate schools. She settled on a Ph.D. program in biomedical sciences at the University of California in San Diego.

In a laboratory managed by Michael Karin, a professor and a world authority on signal transduction pathways that regulate gene expression, Jacinto found herself in the midst of some of the most heady research of the time.

The excitement surrounding protein kinesis — ground-breaking work at the time — quickly overtook Jacinto’s interest in reproduction hormones. Today, she says the course of her career was strongly influenced by Karin’s laboratory.

Jacinto says the experience was both thrilling and stressful. There was such intense interest in the science at the time, she says, and such fierce competition among the students for Karin’s time and attention.

At the University of Switzerland in Basel, Jacinto found herself in a more comfortable environment, studying yeast genetics and working alongside Michael Hall, whose research led to the identification of TOR, which continues to influence the development of immunosuppressant medicines.

Jacinto’s own research in Hall’s laboratory led to the discovery that mTOR — again, the “m” refers to mammalian — creates two protein complexes, mTORC1 and mTORC2. While the two are considered a pair, they work differently: mTORC2 is not inhibited by the drug rapamycin.

“No one knew the function of mTORC2,” Jacinto said. “If mTOR is doing something important, then mTORC2 could have a critical role in cell growth and we could target that as well,” she said. “The job was to figure out what it does.”

In 2004, Jacinto left Switzerland to accept the position at the University of Medicine and Dentistry-Robert Wood Johnson Medical School. In her Piscataway laboratory, she has been able to advance her understanding of mTORC2’s function in the proliferation of cells.

Kinzy, who helped to recruit Jacinto during the school’s international search, remembers being impressed by the young scientist’s work. “She had this unique view of some unanticipated roles of the mTOR pathway,” Kinzy says.

Basic research is considered methodical, time-consuming and expensive and the scientists who do it usually divide their time between teaching and managing research in the lab. Jacinto oversees a research group of five.

“She is a person you bring into an institution,” Kinzy says, “and she becomes a catalyst because she brings great energy and ideas.”

While Kinzy describes Jacinto as an adept collaborator, she is also an advocate of her own ideas and someone who actively solicits feedback. “You’ve got the graceful art of self promotion when you can talk about your work and get others excited about it,” she says.

It may be a particularly good asset for a scientist to have when she is also responsible for raising money to help advance her research. Earlier this year Jacinto applied for a portion of the $9 million in grant money that Stand up to Cancer makes available to young scientists doing cutting-edge cancer research.

Stand up to Cancer, a charitable program of the Entertainment Industry Foundation, focuses its efforts on helping to advance research from the lab to the clinic, where it can be tested to determine if it works as a therapy. The program awards its grants after a grueling, months-long review process.

Jacinto, who ultimately won $750,000 in grant money, began as one of 188 applicants whose letters were reviewed by a 38-member committee, which includes prominent scientists and physicians. The committee chose 43 semi-finalists who were asked to submit full research proposals and then invited 18 to come in for interviews. Thirteen grants were awarded.

Richard Kolodner, one of the scientists who participated in the review of Jacinto’s grant application, acknowledges the intensity of the process. “(The interview) could have been the most serious interview she’s had in her life,” he says. “She had to come into a room and submit to questions from some very serious scientists.”

“She floated to the top of a very tough competition,” he says.

Targeted therapy is one of the latest strategies in the fight against cancer, but there are no guarantees that regulating one protein will make enough of a difference, just as there isn’t a guarantee that a treatment will work effectively for everyone.

Jacinto’s devastation over her daughter’s illness may be more profound because of what she knows about cancer and how it proliferates.

Her daughter’s doctors have assured her that their young patients often fare well with the standard treatment — a combination of chemotherapy drugs. Yet Jacinto is like any other parent of an ill child who is left clinging to hope that the doctors are correct.

“Hopefully, she responds,” Jacinto says. “Knowing what I know about cancer and how things can go wrong and so badly, I just hope they found it early enough.”

The hope underlying Jacinto’s work was always that she did not find something that would help cure a disease, then she might discover a piece of the puzzle that could help create a clearer picture of what triggered it. “As scientists we’re interested in understanding things. Finding a cure is considered a plus,” Jacinto said.

“All of a sudden, since my daughter’s diagnosis, it’s made me think more about how it’s all very urgent,” she says. “A lot of cancer patients are out there relying on us to make discoveries.”

Researchers are increasingly interested in exploiting this tendency with drugs that target cancer cells’ altered metabolism.

Cancer cells’ sugar cravings arise partly because they turn off their mitochondria, power sources that burn glucose efficiently, in favor of a more inefficient mode of using glucose. They benefit because the byproducts can be used as building blocks for fast-growing cells.

Scientists at Winship Cancer Institute of Emory University have shown that many types of cancer cells flip a switch that diverts glucose away from mitochondria. Their findings suggest that tyrosine kinases, enzymes that drive the growth of several types of cancer, play a greater role in mitochondria than previously recognized.

The results also highlight the enzyme PDHK (pyruvate dehydrogenase kinase) as an important point of control for cancer cell metabolism.

The results were published online Thursday by the journal Molecular Cell.

“We and others have shown that PDHK is upregulated in several types of human cancer, and our findings demonstrate a new way that PDHK activity is enhanced in cancer cells,” says Jing Chen, PhD, associate professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. “PDHK is a very attractive target for anticancer therapy because of its role in regulating cancer metabolism.”

Chen and Sumin Kang, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine, are co-corresponding authors. Postdoctoral fellows Taro Hitosugi, Jun Fan and Tae-Wook Chung are co-first authors of the paper. Co-authors at Emory include Georgia Chen, PhD, Sagar Lonial, MD, Haian Fu, PhD, and Fadlo Khuri, MD. Collaborators at Yale University, Novartis and Cell Signaling Technology contributed to the paper.

Chen and his colleagues started out studying the tyrosine kinase FGFR1, which is activated in several types of cancer. Tyrosine kinases attach a phosphate to other proteins, making them more or less active. They found that FGFR1 activates the enzyme PDHK, which has a gatekeeper function for mitochondria.

“We used FGFR1 as a platform to look at how metabolic enzymes are modified by oncogenic tyrosine kinases,” Chen says. “We discovered that several oncogenic tyrosine kinases activate PDHK, and we found that many of those tyrosine kinases are found within mitochondria.”

This was a surprise because tyrosine kinases are usually thought to drive growth by being active next to the cell membrane, Chen says.

Introducing a form of PDHK that is insensitive to tyrosine kinases into human cancer cells forces the cells to grow more slowly and form smaller tumors in mice, they found. This indicates that PDHK could be a target for drugs that specifically target cancer cells’ altered metabolism.

The experimental drug dichloroacetate (DCA), which inactivates PDHK, is being used in new clinical trials for cancer. Chen is collaborating with Haian Fu, professor of pharmacology and director of the Emory Chemical Biology Discovery Center, to find other, more potent inhibitors of PDHK.

HOUSTON — An inflammation-promoting protein triggers deactivation of a tumor-suppressor that usually blocks cancer formation via the NOTCH signaling pathway, a team of researchers led by scientists at The University of Texas MD Anderson Cancer Center reports today in Molecular Cell.

Working in liver cancer cell lines, the team discovered a mechanism by which tumor necrosis factor alpha (TNFα) stimulates tumor formation, said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson’s Department of Molecular and Cellular Oncology. Hung also is MD Anderson’s vice president for basic research.

“We’ve discovered cross-talk between the TNFα inflammation and NOTCH signaling pathways, which had been known to separately promote cancer development and growth,” Hung said. Liver cancer is one of several cancers, including pancreatic and breast, associated with inflammation.

Their findings have potential implications for a new class of anti-cancer drugs currently in clinical trials. “Pharmaceutical companies are developing NOTCH inhibitors,” Hung said. “TNFα now presents a potential resistance mechanism that activates NOTCH signaling in a non-traditional way.”

Pathways also unite in colon, lung, prostate cancers

“In addition, co-activation of these two pathways was also observed in colon, lung and prostate cancers, suggesting that the cross-talk between these two pathways may be more generally relevant,” Hung said.

However, TNFα also presents an opportunity to personalize therapy, Hung said. The presence of TNFα or a separate protein that it activates called IKK alpha may serve as useful biomarkers to guide treatment.

“If a patient has only NOTCH activated, then the NOTCH inhibitor alone might work. But if TNFα or IKKα are also activated, then the NOTCH inhibitor alone might not work very well and combination therapy would be warranted,” Hung said.

“We’ll try this in an animal model and then go to clinical trial if it holds up,” Hung said.

A path from inflammation to liver cancer

In a series of experiments, Hung and colleagues connected the following molecular cascade:

• TNFα, a proinflammatory cytokine, signals through a cell’s membrane, activating IKKα, a protein kinase that regulates other proteins by attaching phosphate groups (one phosphate atom, four oxygen atoms) to them.
• IKKα moves into the cell nucleus, where it phosphorylatesFOXA2, a transcription factor that normally fires up the tumor suppressor NUMB.
• NUMB usually blocks a protein called NICD, the activated portion of NOTCH1 that slips into the cell nucleus to activate genes that convert the normal cell to a malignant one.
• But when FOXA2 is phosphorylated, it does not activate NUMB. With NUMB disabled, NOTCH1 is activated. New understanding, new targets for cancer therapy

In liver cancer (hepatocellular carcinoma) tumors, IKKα, the phosphorylated version of FOXA2 and NOTCH1 are expressed more heavily than in normal liver tissue. Expression of all three is correlated in liver cancer tumors, the team found.

The authors conclude that identifying the link between TNFα and NOTCH1 pathways provides a new starting point for understanding the molecular basis for TNFα-related tumor growth and for identifying new targets for cancer therapy.

Finding ways to inhibit FOXA2 phosphorylation or to activate NUMB would provide new options for treating and perhaps preventing cancer, Hung said.

Co-authors with Hung are first author Mo Liu, Dung-Fang Lee, Chun-Te Chen, Hong-Jen Lee, Chun-Ju Chang, Jung-Mao Hsu, Hsu-Ping Kuo, Weiya Xia, Yongkun Wei, Chao-Kai Chou, and Yi Du, all of MD Anderson’s Department of Molecular and Cellular Oncology; Liu also is a graduate student in The University of Texas Graduate School of Biomedical Sciences at Houston, a joint program of MD Anderson and The University of Texas Health Science Center at Houston; Chia-Jui Yen, National Cheng Kung University College of Medicine, Tainan, Taiwan; Long-Yuan Li, Wei-Chao Chang and Pei-Chun Chiu of the Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Debanjan Dhar and Michael Karin, Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego; and Chung-Hsuan Chen, The Genomics Research Center, Academica Sinica, Taipei, Taiwan. Wei-Chao Chang also is associated with Academic Sinica.

Funding for this research was provided by the National Cancer Institute, including MD Anderson’s Cancer Center Support Grant from the NCI, National Science Council of Taiwan, Taiwan Department of Health; The MD Anderson-China Medical University and Hospital Sister Institution Fund, the Kadoorie Charitable Foundation and a research assistant scholarship to Mo Liu by the University of Texas Graduate School of Biomedical Sciences at Houston.

Cancer cells are essentially immortal. The acquisition of an unlimited capacity to divide – the process of immortalization – is a central event in the genesis of tumors. Normally, cells are subject to stringent mechanisms which control their proliferation. Together these ensure that pre-malignant cells are induced to enter a senescent, non-dividing state or to undergo apoptosis, i.e. commit suicide.

A research team led by Professor Heiko Hermeking and Dr. Antje Menssen from LMU’s Institute of Pathology has now discovered how the regulatory protein c-MYC subverts these controls, thus facilitating the growth of tumors. High levels of c-MYC, which are present in most tumor cells, activate SIRT1, an enzyme that inhibits both senescence and apoptosis. The new results show that the two proteins actually form a positive feedback loop, in that SIRT1 also promotes the activity of c-MYC. Normal cells avoid this vicious circle because they keep the gene that codes for c-MYC turned off, unless they receive growth-promoting signals. In tumor cells, this mechanism no longer functions and the cells can proliferate unchecked.

Their latest findings have implications for cancer treatment, as Menssen explains: “Our results indicate that tumor types in which c-MYC plays a crucial role, such as lymphomas and colon or breast cancers, should be especially susceptible to pharmacological inhibitors that interrupt the feedback loop. In particular, combinations of drugs that interact with different components of the loop could provide a new route to effective therapies of these malignancies.” (PNAS 19.-23.12)

The c-MYC protein is involved in the control of many basic biological functions, including cell growth and division. It is therefore vital for processes that require cell proliferation, such as embryonic development and the generation of all the cell types in the blood. Overproduction of c-MYC, on the other hand, can have lethal consequences for the organism. Continuous synthesis of c-MYC is a prominent feature of immortalized cells, which divide in an uncontrolled fashion and thus facilitate the formation of tumors. Normally, multiple mechanisms serve to regulate the expression of the gene for c-MYC, and keep the level of the protein present in cells within appropriate limits. In essence, the gene is activated only when a cell is instructed to do so by specific growth-promoting signals. If this failsafe mechanism is disabled, a second internal system switches in. This back-up circuit ensures that increased concentrations of c-MYC cause premature cell senescence (which makes cells unresponsive to growth signals) and induce programmed cell death. However, in tumor cells, these safeguards no longer function – and in some tumors and cell types it has emerged that c-MYC itself is responsible for knocking them out. “How c-MYC achieves this has remained largely unclear,” says Hermeking. In order to clarify the mechanisms involved, the researchers focused on the enzyme SIRT1 as a possible accomplice of c-MYC. As Hermeking explains, “SIRT1 seemed to us a likely candidate because a related enzyme has been shown to play a role in extending the lifespan of cells in lower organisms. In human cells, SIRT1 is known to inhibit a regulator that promotes senescence and programmed cell death.”

The hunch turned out to be correct, since the team, which included molecular biologists from Aachen University and the Karolinska Institute in Stockholm, was able to show that c-MYC actually enhances SIRT1 function in a number of different ways. First, it activates NAMPT (nicotinamide phosphoribosyltransferase), which is responsible for the synthesis of a molecule required for the action of SIRT1. Secondly, c-MYC represses an inhibitor of SIRT1, so releasing a further brake on its function. Finally, SIRT1 itself potentiates these effects by reducing the rate of degradation of c-MYC. The end result is a positive feedback loop which drives the continuous accumulation of both SIRT1 and c-MYC in the cell.

The c-MYC protein is synthesized in large amounts in most tumors. Furthermore, in certain cancers, such as lymphomas and cancers of the colon and the breast, c-MYC is known to play a causative role in the origin of the primary tumor. In these cases, mutations in the c-MYC gene itself, or in genes that regulate its expression, result in constant production of the c-MYC protein. The new findings are thus of particular relevance for the development of new treatment options for these types of cancer, since one would expect them to be highly sensitive to direct inhibition of SIRT1 or NAMPT. Interestingly, several studies in recent years have revealed that levels of NAMPT are also increased in many tumors. Indeed, a chemical inhibitor of NAMPT is already undergoing clinical trials. “Our study strongly suggests that the feedback loop initiated by excess c-MYC drives the overproduction of NAMPT. A combination of drugs that would allow us to inhibit the actions of both SIRT1 and NAMPT might therefore have a synergistic effect and could open up new therapeutic possibilities,” Menssen points out.

In addition, the new findings raise questions regarding the allegedly positive effect of a daily glass of red wine on lifespan. The putative health benefits of this regime have been attributed in part to the activation of SIRT1 by the compound resveratrol, which is found in red wine. Indeed, commercial development of pharmacological SIRT1 activators such as resveratrol is already underway – in the hope that they will slow the aging process and block the development of obesity and diabetes. In this context, Hermeking advises caution: “In the light of our results, these agents should only be used after further extensive study.”

More information: The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1 inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop. A. Menssen, P. Hydbring, K. Kapelle, J. Vervoorts, J. Diebold, B. Lüscher, L.- G. Larsson, H. Hermeking. PNAS Early Edition 19.-23.12.2011 doi: 10.1073/pnas.1105304109

Provided by Ludwig-Maximilians-Universitat Munchen

Matthew Herper, Forbes Staff

Christopher Hitchens, quite famously, did not believe in miracles. His death is a reminder that we shouldn’t, either – even when they’re the scientific kind.

Hitchens, like Steve Jobs, was among the first patients to benefit from a very new technology: the use of DNA sequencing to pick cancer drugs that might have a better chance of slowing a tumor’s growth.

Cells become cancerous because of mutations in their DNA that make them stop behaving as discrete parts of the body and instead cause them to multiply like crazy and run amok. Once a cell is cancer, its genes get twisted and re-arranged even more. The idea is that by identifying some of these mutations, doctors can figure out which drugs are most likely to stop or slow tumor growth and prolong life.

Jobs was so excited by this idea that he told his biographer, Walter Isaacson, that he could be among the first to outrun cancer this way or be among the last to die from it. Both DNA from Jobs’ tumor and Jobs’ own cells was sequenced — the most expensive and exhaustive way to look for tumor-causing defects. (A cheaper way is to just look at genes known to correlate with effectiveness for existing drugs in some cancers.)

Characteristically, Hitchens did not get nearly as excited as Jobs did about the prospect, but he still seemed filled with hope. “At least it spares me some of the boredom of being a cancer patient because what I’m going through is very absorbing and positively inspiring,” he told the Daily Telegraph. “But if it doesn’t work, I don’t know what they could try next.”

Also characteristically, the story of sequencing Hitchens’ tumor is full of larger-than-life debates about belief and nonbelief, God and the absence thereof. He was approached by Francis Collins, a devout Christian and head of the National Institutes of Health. A decade ago, Collins led the government-funded Human Genome Project, and he became deeply involved in Hitchens’ care.

In this video, aside from responding to the question, “Well Christopher, how are you feeling,” with “Well, I’m dying, but so are you,” Hitchens talks movingly about Collins, who he calls a great American, “one of the devout human beings I’ve ever met.”

Hitchens did find a drug that seemed to address one of his tumor’s mutations – it was reportedly Novartis’ Gleevec, the first targeted cancer drug – and that may have spared him some rounds of chemotherapy. But the medicine did not, of course, save him. Nor did it save Jobs.

According to Hitchens, Collins told him that he’s never seen anything in his medical career that could be called a miracle. That’s probably worth remembering as we begin to move into an era where many patients’ tumors will be sequenced. M.D. Anderson, where Hitchens died, has been trying to use DNA sequencing as a standard step in picking experimental drugs for patients; so have other cancer centers. One company, Foundation Medicine, which counts Google Ventures among its investors, is trying to turn this into a business model. Makers of DNA sequencing technology, including Illumina, Life Technologies, and Pacific Biosciences have been talking about the business opportunity for years.

This make sense because caring for late-stage cancer patients is so expensive, and so often futile, that even a costly technology like DNA sequencing (the price is dropping at an amazing rate but it’s still $5,000 or so for a full genome) could easily lead to improvements. But this technology is still in its early days, and it is not saving many lives just yet.