Volume 17 Issue 3, March 2011

Established in 1894 as the Massachusetts Public Health Laboratories, MassBiologics is now the only nonprofit, licensed vaccine and biologics manufacturer and research center in the US. Leading the charge is Executive Director Donna Ambrosino, who sat down to speak with Elie Dolgin at MassBiologics's brand new research center, which opened last summer in the outskirts of Boston.

Patient-specific stem cells have been heralded as the next frontier in regenerative medicine. Although most therapies are probably a decade or more away, for one life-threatening skin disease the first clinical trials involving induced pluripotent stem cells may begin as early as 2014. Monya Baker investigates.

Cancer drugs have become more expensive over the past few years, leading many people to question whether the treatments are really worth their high costs. But despite the sticker shock, cancer medicines have provided good value for money.

Mitochondrial fission-fusion and trafficking are altered in the fatal neurodegenerative disorder Huntington's disease. Huntingtin is now shown to function directly in these processes by binding the mitochondrial fission factor dynamin-related protein-1 (DRP1). Mutant huntingtin binds more tightly to DRP1, leading to increased mitochondrial fission and neuronal death, highlighting DRP1 as a potential therapeutic target in Huntington's disease (pages 377–382).

X-box–binding protein-1 (XBP-1) increases insulin sensitivity by activating endoplasmic reticulum capacity during feeding to control glucose homeostasis, a function severely impaired in obesity. But XBP-1 can also increase glucose tolerance in obese and diabetic mice by blocking gluconeogenesis, independent of its effect on insulin sensitivity, opening new avenues for type 2 diabetes therapies (pages 356–365).

Finding mechanisms of viral resistance and new ways to tackle chronic hepatitis will help find a cure for this disease. In 'Bench to Bedside', Christopher Walker and Benoît Callendret highlight studies showing that overcoming immune exhaustion during chronic infection by blocking several inhibitory pathways of T cells may restore an adequate immune response. In 'Bedside to Bench', Lawrence Corey, Joshua Schiffer and John Scott discuss recent advances in antiviral therapy with protease inhibitors and the findings of a mathematical model that predicts possible single and double mutations prior to antiviral therapy.

Advances in cancer research are enabling fast-paced discovery and translation of results into potential clinical tools. Here we consider some of the most influential findings of the past two years, selected by experts in the cancer field.

In recent years, Salmonella has tainted foods including spinach, peanut butter and eggs, sickening thousands of people in the process. But researchers hope that these microbes will make headlines for a better reason: curing cancer. They want to harness Salmonella's special ability to thrive in oxygen-deprived conditions to target regions of solid tumors that are normally immune to conventional therapies. Elie Dolgin reports.

Which are the most relevant recent discoveries in cancer research? Which advances in cancer biology, drug discovery and clinical practice have been the most important for the field?

A continuing quest in clinical oncology is to effectively eliminate tumors without major side effects. But drugs rationally tailored against specific tumors and predictive markers for patient selection are very limited, and their identification is challenging. A phase 1 study has provided proof of concept for the use of PARP inhibitors in tumors from individuals carrying BRCA mutations—a remarkable success in rational drug design and translational research.

Inflammation is an important component of the tumor microenvironment; however, the mechanisms through which immune cells might promote tumorigenesis are unclear. A recent study indicates that B cells and antibodies have a key role in orchestrating macrophage-driven, tumor-promoting inflammation, suggesting that modulating the pathways involved might be of therapeutic benefit in cancers driven by chronic inflammation.

Although the rapid development of drug resistance is a known problem with targeted cancer therapies, recent studies have uncovered other surprises with RAF kinase inhibitors. These drugs can paradoxically activate downstream ERK signaling in some settings, with important implications for their clinical use.

Therapeutic resistance is a key roadblock to effective cancer treatment and can occur through various mechanisms. A recent study characterized a previously unknown, reversible mechanism of drug resistance mediated by an altered chromatin state, suggesting that cancer cell populations can use a dynamic strategy to ensure their survival when challenged by therapeutic intervention.

Neuroblastoma is a fatal childhood cancer, but lack of knowledge about the underlying causative genes has hampered the development of effective therapies. The identification of anaplastic lymphoma kinase (ALK) mutations as drivers of neuroblastoma has indicated that targeted therapy with ALK inhibitors might be a valuable strategy in the fight against this lethal cancer.

Recently characterized IDH1 and IDH2 mutations in leukemia and glioblastoma have introduced a fascinating cancer-specific role for metabolic genes essential to cellular respiration. Studies also link aberrant IDH1 and IDH2 activity to an altered metabolite profile, an observation that may have broad implications for both cancer epigenetics and clinical management of disease.

Mice lacking kinase suppressor of Ras-1 (Ksr1) are highly susceptible to Pseudomonas aeruginosa, a bacterium that often causes infections in people with cystic fibrosis. Ksr1 recruits inducible nitric oxide synthase and heat shock protein-90 to release nitric oxide upon infection, enhancing bactericidal activity.

Polyubiquitination of the tumor suppressor p53 (encoded by TP53) regulates its stability by targeting it for degradation. Wu et al. now report that UBE4B, an E3 and E4 ligase, is a key enzyme in this process and that overexpression of UBE4B in some brain tumors is associated with reduced p53 abundance, suggesting a previously unknown mechanism blocking p53 function in cancer.

Insulin dials down endogenous hepatic glucose production after a meal by deactivating the transcription factor FoxO1. In a mouse model of insulin resistance, Umut Ozcan and his colleagues now show that hepatic overexpression of Xbp-1s, a factor involved in the cell stress response, leads to the protein degradation of FoxO1, thus reducing serum glucose levels. These results suggest a way to bypass one aspect of insulin resistance.

The STEP HIV-1 vaccine trial failed to protect volunteers from infection, but whether vaccine-driven immune responses affected the profile of viral variants in infected individuals was unknown. By analyzing nucleotide sequences and predicted T cell epitopes in viruses from newly infected trial participants, Rolland et al. now report that the degree of viral divergence from vaccine-encoded inserts suggests that vaccine-induced T cell responses indeed influenced the viral repertoire, a finding that might be harnessed in future vaccine design.

Discriminating between active and latent infection with Mycobacterium tuberculosis (Mtb) is a protracted and complicated process, which can affect the timeliness of treatment decisions. Harari et al. now report that the cytokine profiles of Mtb-specific CD4⁺ T cells characterized by a polychromatic flow cytometry assay can distinguish latent infection from active disease.

Huntington's disease is characterized by mitochondrial dysfunction and neuron death. Now, Ella Bossy-Wetzel and her colleagues report that the aberrant interaction of mutant huntingtin protein with the mitochondrial fission protein DRP1 results in DRP1 activation. Blocking DRP1 activity can reduce mutant huntingtin–induced cell death.

The invasive nature of intravascular ultrasound and other approaches used to screen for atherosclerosis has prompted Marcus Makowski and his colleagues to look for a more noninvasive means of assessing plaque burden. Their new elastin–specific, gadolinium-based MR contrast takes advantage of changes in elastin content that occur during plaque development. Use of the new contrast agent is shown in an Apoe transgenic mouse model of accelerated atherosclerosis.

Which new findings are having the greatest influence on cancer research today? We asked experts to help identify the most important recent papers that are shaping the direction of cancer research. Here we present their selections and thoughts on the impact of current research directions on future clinical gains.