Category Archives: Cancer

As gene therapy technologies blossom, ddRNAi tries to take root

Posted on by
Reply

shutterstock_133184528Before there was Twitter, there was Facebook, and before that, Friendster. And who can forget MySpace? There’s a similar trend of successive usurping technologies in the fast-moving quest to develop therapeutics capable of modifying the genome. Since the late nineties, we’ve witnessed the rise of several gene-silencing approaches, from “antisense” oligonucleotides and RNA interference (RNAi) to the latest targeted genome-editing techniques, such as those based on zinc finger nucleases or CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology. These rapid developments raise the stakes for companies that have wagered on a particular gene-silencing approach.

Take the case of an approach known as DNA-directed RNAi (ddRNAi). In January, Australia-based Benitec Biopharma received a green light from the US Food and Drug Administration to begin the first human trial of an intravenous viral gene therapy based on ddRNAi. The therapy, dubbed TT-034, is essentially a modified form of adeno-associated virus 8, which naturally infects people but is not pathogenic. In TT-034, the viral DNA has been engineered to encode short hairpin RNAs (shRNAs) that silence three different components of the hepatitis C virus (HCV). The approach is referred to ddRNAi because the shRNA that carries out the gene silencing is continually produced by the cell from a DNA vector. Continue reading →

New classification system proposed for breast cancer types

Posted on by
Reply

Since the late 1970s, clinicians have distinguished breast cancers types according to the presence or absence of certain receptors that sit on the surface of these tumor cells. Depending on the receptors found—namely, the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)—a doctor can get a better sense of the prognosis and which treatments might work.

Now, a study published this week in the Journal of Clinical Investigation proposes a new conceptual framework that classifies breast cancers based on whether the cells possess receptors for other molecules, such as androgen and vitamin D. Under this system, current cancer subtypes would be stratified into one of four groups.

“I’m very excited about this paper,” says Jorge Reis-Filho, a pathologist at the Memorial Sloan Kettering Cancer Center in New York who was not involved in the research. He adds that the proposed classification system could point to new therapies for breast cancers previously categorized as unlikely to respond to treatment.

In the new study, researchers sought to explain some of the diversity observed in human breast tumors by obtaining a more detailed understanding of normal breast cell subtypes. “I approached this question like an evolutionary biologist trying to figure out the ancestry of a species,” says study co-author Tan Ince, a pathologist at the University of Miami Miller School of Medicine.

Ince and his team scanned samples of normal breast tissue for proteins expressed in a “bimodal” or on/off pattern—highly expressed in some cells but completely absent in others. The researchers focused in on the handful of proteins that displayed this pattern. They subsequently characterized 11 previously undescribed subtypes of luminal cells—one of the two major epithelial cell types found in mammary glands—that each expressed distinct combinations of these proteins.

Continue reading →

New techniques could improve reprogrammed-immune-cell treatment of HIV and cancer

Posted on by
Reply

­­­

Recent experiments exploring the use of patients’ own genetically reprogrammed immune cells toward the treatment of chronic diseases such as HIV and cancer have had encouraging and sometimes high-profile results. Yet, these studies have only been conducted in a limited number of individuals, and outcomes have been inconsistent, ranging from complete remission to complete inefficacy.

Now, two teams of researchers have demonstrated a method of using patients’ cells to create long-lived immune cells that target specific HIV and cancer antigens, and appear to resist degradation over time. Their work was published today in two separate papers in Cell Stem Cell.

“Our method has realized the functional rejuvenation and unlimited production of mature cytotoxic T cells with desired antigen-specificity for the first time in vitro,” says Shin Kaneko a stem cell biologist at Kyoto University in Japan and a co-author of the HIV-related study.

Difficulties in previous attempts to extract and reengineer T cells from patients are thought to be due in part to a phenomenon known as ‘cellular senescence’, a type of aging process. Naïve, quiescent T cells can survive for decades in the body. But active T cells, particularly those expanded outside the body in the laboratory, can gradually lose the ability to proliferate and be effective. This can lead to insufficient numbers of active immune cells to combat disease.

“Replicative senescence is likely to be a major issue for adoptive cell therapy,” says Carl June, an immunologist at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. “[These papers] address this issue and are exciting demonstrations of the progress in cell and developmental biology.”

Continue reading →

Metabolic gatekeeper provides new target for disrupting cancer metabolism

Posted on by
Reply

In the 1920s, the German physiologist Otto Warburg proposed that cancer cells generate energy in ways that are distinct from normal cells. Healthy cells mainly metabolize sugar via respiration in the mitochondria, switching only to glycolysis in the cytoplasm when oxygen levels are low. In contrast, cancer cells rely on glycolysis all the time, even under oxygen-rich scenarios. This shift in how energy is produced—the so-called ‘Warburg effect’, as the observation came to be known—is now recognized as a primary driver of tumor formation, but a mechanistic explanation for the phenomenon has remained elusive.

Now, researchers have implicated a chromatin regulator known as SIRT6 as a key mediator of the switch to glycolysis in cancer cells, a finding that could lead to new therapeutic modalities. “This work is very significant for the cancer field,” says Andrei Seluanov, a cancer biologist at the University of Rochester in New York State who studies SIRT6 but was not involved in the latest study. “It establishes the role of SIRT6 as a tumor suppressor and shows that SIRT6 loss leads to tumor formation in mice and humans.”

SIRT6 encodes one of seven mammalian proteins called sirtuins, a group of histone deacetylases that play a role in regulating metabolism, lifespan and aging. SIRT1—which is activated by resveratrol, a molecule found in the skin of red grapes—is perhaps the best known sirtuin, but several of the others are now the focus of active investigation as therapeutic targets for a range of conditions, from metabolic syndrome to cancer. Just last month, for example, a paper in Nature Medicine demonstrated that SIRT6 plays an important role in heart disease.

Six years ago, a team led by Raul Mostoslavsky, a molecular biologist at the Massachusetts General Hospital Cancer Center in Boston, first showed that SIRT6 protects mice from DNA damage and had anti-aging properties. In 2010, the same team established SIRT6 as a critical regulator of glycolysis. Now, reporting today in Cell, Mostoslavsky and his colleagues have shown that SIRT6 function is lost in cancer cells—thus, definitively establishing SIRT6 as a potent tumor suppressor.

Continue reading →