Investigators at UC San Diego find that Cyclin D essential to regulating cell cycle progression – the process of cell division and replication – activates a key tumor suppressor, rather than inactivating it as previously thought. The finding fundamentally change the understanding of G1 cell cycle regulation and the molecular origins of many associated cancers.

The study, published in the journal eLife, completely upend what was thought to be a fundamental knowledge of cell cycle progression in all cancer cells driven by one of the most common genetic pathways mutated in cancer, namely the p16-cyclin D pathway.

Understand the relationship of Cyclin D with cancer

Cyclin D is synthesized during the first stage of cell replication and is believed to help drive the complex and multi-stage process. It involves in interaction with the retinoblastoma (Rb) protein, whose function is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. As shown in relative studies, Rb acts as a tumor suppressor.

However, mutated or dysfunctional Rb is linked with several major cancers and Cyclin D has long been regarded as an oncogene that promotes cancer because it was believed to inactivate the Rb tumor suppressor function through a process called phosphorylation, which involves phosphate molecules being added to proteins, essentially turning them on or off.

Investigators carefully counted the number of phosphates added to Rb during cell cycle progression. There are as many as 14, but the scientists found that cyclin D adds just a single phosphate at one, and only one of the 14 locations essentially make 14 different versions of the Rb tumor suppressor during the early G1 phase. The single phosphate serves to activate Rb, not inactivate it as had been thought for over 20 years.

Recently, a study shows that Prophage, a new brain cancer vaccine, can double life expectancy for patients with glioblastoma multiforme (GBM). The median life expectancy in 50% of patients newly diagnosed with GBM increased to 2 years when the drug was given in addition to standard treatment. After 2 years 33% of patients remain alive and continue to have survival rates followed.

46 newly diagnosed GBM patients, treated at 8 centers across the US, were recruited into the Phase 2, single-arm and open-label study. In addition to Prophage vaccination the patients were given the standard forms of treatment which included radiation, surgical resection and temozolomide.

Therapeutic prospect of new cancer vaccine

The new autologous cancer vaccine Prophage is derived from each patient’s own tumor tissue that has been surgically removed, implying that the vaccine is customized to each individual. Most cancers result from random mutations that leads to heterogeneity of patient group. Since Prophage is made from the patient’s tissue, it’s possible to assist immune system to specifically target each tumor.

The study data suggests that the immune response generated by Prophage is resulting in an increase in survival rates that are significantly longer than what has historically been seen in GBM patients. Additionally, a median progression-free survival of nearly 18 months is approximately 2-3 folds longer than with traditional treatments alone. These support a conclusion that the new vaccine can play an important role in changing the standard treatment options for patients with GBM.

Summary of brain tumor vaccines

Insight into glioblastomas

Glioblastomas can grow rapidly, resulting in that median survival can be as low as 14.6 months and two-year survival rates are only about 30 percent. As we know, the tumors grow from astrocytes, the star-shaped cells that make up the brain’s supportive tissue. They are generally highly malignant because they reproduce quickly.

GBM tumors account for about 17 percent of all primary brain tumors, affect more men than women, and increase in frequency with age. Their cause is unknown, and they are very difficult to remove because of their finger-like tentacles. Treatment of GBM is also difficult because of the many different types of cells present in the tumors. Some of the cells respond well to treatment, while others may show no effect.

Malignant melanomas that arise from the iris, ciliary body, and choroid layers of the eye-collectively referred to as uveal melanomas—represent the most common primary cancer of the eye and the second most common form of melanoma. Until recently, the identification of effective therapies for metastatic uveal melanoma has been hampered by a lack of known driver mutations. This situation has changed in recent years with the discovery of several common driver mutations, which has opened the door to rational targeted therapies.

Mutually exclusive mutations in the G protein-coupled receptor (GPCR) alpha subunits GNAQ and GNA11 (encoding Gq and G11 proteins, respectively) are present in ∼85% of uveal melanocytic tumors, including benign nevi, primary melanomas of all stages, and metastatic lesions. This spectrum suggests that GNAQ/11 mutations occur early and may even represent initiating events in tumorigenesis. These mutations occur as single amino acid substitutions at residues Q209 or R183, and they abrogate the intrinsic GTPase activity that normally serves to inactivate the subunit. As such, these inactivating mutations result in constitutive activation of oncogenic Gq/11 subunits. The recessive nature of these mutations at the molecular level, despite their dominant action at the cellular level, has posed a major challenge for direct pharmacologic inhibition. Instead, most efforts have focused on inhibiting downstream targets of activated Gq/11. The best understood target of Gq/11 is phospholipase C beta (PLCβ), which cleaves phosphatidylinositol (4,5)-bisphosphate (PIP2) to yield diacylglycerol (DAG) and inositol triphosphate (IP3). Both products promote stimulation of protein kinase C (PKC), which leads to activation of the mitogen-activated protein kinase (MAPK or MEK) pathway and cell proliferation. MEK and PKC inhibitors inhibit the proliferation of Gq/11 mutant uveal melanoma cell lines in vitro. Yet, clinical trials so far have shown little or no activity of such agents in patients with metastatic uveal melanoma, raising the question of whether there may be other targets that are critical for therapeutic inhibition in cancers harboring oncogenic forms of Gq/11.

One such target may be the Hippo tumor suppressor pathway, which controls tissue growth and cell fate through the regulation of cell proliferation and apoptosis . Key effectors of the pathway include the homologous oncoproteins YAP and TAZ, which promote tissue growth by regulating the activity of transcription factors such as TEADs and SMADs. In most proliferating cells, YAP is localized in the nucleus in its active form. Hippo pathway signaling leads to phosphorylation of YAP by the serine/threonine-protein kinases LATS1/2, resulting in YAP inactivation and retention in the cytoplasm and degradation via the proteasome.

Feng et al. and Yu et al. publicized studies showing that Gq/11 mutants found in uveal melanoma promote tumorigenesis by activating YAP. Mutant Gq/11, but not wild-type Gq/11, was found to trigger dephosphorylation and nuclear localization of YAP, associated with YAP-dependent transcription. Importantly, this activity of mutant Gq/11 is independent of PLCβ. In uveal melanoma cell lines and human tumor samples, there was a strong correlation between the presence of Gq/11 mutations and activated YAP, as indicated by its nuclear localization and increased levels of unphosphorylated YAP.

The question then arises as to whether this YAP activation by mutant Gq/11 is mediated solely through inhibition of LATS1/2. In their current article and in a recent publication by the same group show that activation of YAP by mutant Gq requires the guanine nucleotide exchange factor, Trio, and downstream small GTPases RhoA and Rac1. Activation of RhoA and Rac1 induces actin polymerization of G-actin to F-actin, triggering dissociation of the cytoskeletal-associated protein angiomotin (AMOT) from YAP, thereby allowing YAP to translocate from the cytoplasm to the nucleus to activate YAP-dependent transcription. Thus, mutant Gq/11 may activate YAP not only by inhibiting LATS1/2, but also by promoting actin polymerization independently of the canonical Hippo pathway.

Although these findings are promising, it is unlikely that inhibition of mutant Gq/11 signaling alone will be sufficient for treating metastatic uveal melanoma. Mutant Gq and G11 are relatively weak oncoproteins that are only able to transform immortalized melanocytes that have been genetically altered to be deficient in the p53 and p16/CDK4/RB pathways. Nevertheless, these findings will play an important role in the ongoing quest for effective therapy against metastatic uveal melanoma.

Scientists studying the effects of the diabetes drug metformin on treating a variety of cancers in various clinical trials previously have cited the activation of a molecular regulator of cell metabolism—AMPactivated protein kinase (AMPK)—as suppressing tumor growth. However, a new study suggests that the activation of AMPK may actually fuel cancer growth.

The study’s leaders, from Cincinnati Children’s Hospital in Ohio, also suggest that researchers working on clinical trials of metformin and cancer carefully evaluate their clinical data. They are not saying that these trials should be stopped, but rather, that the drug’s mechanism of cancer suppression is unclear.

The Cincinnati researchers reported on extensive laboratory tests indicating that metformin does stop cancer, but not by activating AMPK. The tests, on glioblastoma cells, found that the drug inhibits a molecule called mammalian target of rapamycin (mTOR), which has been linked to many cancers. Metformin also suppresses the action of insulin and insulinlike growth factors, which support cancer growth. Their studies also found that AMPK potentially works as a tumor growth supporter and that researchers studying metformin in cancer clinical trials should be cautious in interpreting their data.

The researchers conducted experiments involving laboratory cell cultures of human glioblastoma cells and glioblastoma tumors transplanted in mice. Compared with normal human and mouse tissue, the researchers found that AMPK was highly active in human and mouse glioblastoma cells. They then treated the cancer cells with metformin and conducted a ser ies of genetic tests to determine the molecular pathways it uses to stop the cancer growth. Those tests showed clearly that metformin directly inhibited the mTOR pathway and the cancer by promoting the interaction of 2 upstream molecules that stop the pathway’s function.

AEG-1/MTDH/LYRIC has been shown to promote cancer progression and development. Overexpression of AEG-1/MTDH/LYRIC correlates with angiogenesis, metastasis, and chemoresistance to various chemotherapy agents in cancer cells originating from a variety of tissues. Xiangbing Meng focused on the role of AEG-1/MTDH/LYRIC in drug resistance. Their mechanistic studies have shown that AEG-1/MTDH/LYRIC is involved in classical oncogenic pathways including Ha-Ras, myc, NFκB, and PI3K/Akt. AEG-1/MTDH/LYRIC also promotes protective autophagy by activating AMP kinase and autophagy-related gene 5.

Another reported mechanism by which AEG-1/MTDH/LYRIC regulates drug resistance is by increasing loading of multidrug resistance gene (MDR) 1 mRNA to the polysome, thereby facilitating MDR1 protein translation. More recently, a novel function for AEG-1/MTDH/LYRIC as an RNA-binding protein was elucidated, which has the potential to impact expression of drug sensitivity or resistance genes. Finally, AEG-1/MTDH/LYRIC acts in microRNA-directed gene silencing via an interaction with staphylococcal nuclease and tudor domain containing 1, a component of the RNA-induced silencing complex. Altered microRNA expression and activity induced by AEG-1/MTDH/LYRIC represent an additional way that AEG-1/MTDH/LYRIC may cause drug resistance in cancer. The multiple functions of AEG-1/MTDH/LYRIC in drug resistance highlight that it is a viable target as an anticancer agent for a wide variety of cancers.

Researchers have developed a personalized tool that helps to predict which men face a high risk of being overdiagnosed with prostate cancer. Up to 42% of men are overdiagnosed with the disease, leading to unnecessary treatment and serious side effects.

To address that problem, researchers from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle have developed a nomogram, a graphical calculating device that incorporates a patient’s age, prostate-specific antigen level, and Gleason score to determine the likelihood that a screening-detected prostate cancer has been overdiagnosed. Investigators intend for the tool to be a guide in better determining personalized treatment options.

To develop the nomogram, the researchers created a virtual population model of US men aged 50 to 84 years from 1975 to 2005. They applied existing data regarding prostate-specific antigen levels, biopsy practices, and cancer diagnosis patterns to learn about cancer progression in patients with and without screening. Next, they overlaid screening and biopsy patterns on the model to determine when the men would have been diagnosed with and without screening and which ones would have died of other causes. The data enabled the researchers to develop a prediction model that estimates the likelihood of overdiagnosis on a scale of 2.9 to 88.1.

Although nomograms are common in prostate cancer research, the authors say that to their knowledge theirs is the first to examine the likelihood of prostate cancer overdiagnosis on an individual level. They plan to develop an interface and test the nomogram in a pilot study tentatively planned for later this year.

To identify new genetic risk factors for cervical cancer, scientists conducted a genome-wide association study in the Han Chinese population. The initial discovery set included 1,364 individuals with cervical cancer (cases) and 3,028 female controls, and they selected a ‘stringently matched samples’ subset (829 cases and 990 controls) from the discovery set on the basis of principal component analysis; the follow-up stages included two independent sample sets (1,824 cases and 3,808 controls for follow-up 1 and 2,343 cases and 3,388 controls for follow-up 2).

They identified strong evidence of associations between cervical cancer and two new loci: 4q12 (rs13117307, Pcombined, stringently matched = 9.69 × 10−9, per-allele odds ratio (OR)stringently matched = 1.26) and 17q12 (rs8067378, Pcombined, stringently matched = 2.00 × 10−8, per-allele ORstringently matched = 1.18). They additionally replicated an association between HLA-DPB1 and HLA-DPB2 (HLA-DPB1/2) at 6p21.32 and cervical cancer (rs4282438, Pcombined, stringently matched = 4.52 × 10−27, per-allele ORstringently matched = 0.75). Their findings provide new insights into the genetic etiology of cervical cancer.

Recently, there is a major finding that a class of drug in the treatment of leukemia has the unexpected side-effect of boosting immune responses against many different cancers. This make it by inactiving PI3K p110δ that restrains the antitumour immune response. The good news is that because the drugs used in this study are already being used in the clinic, people could see rapid translation of this research into patient benefit.

As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. However, it’s reported that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. Investigators  demonstrate that p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.

A major step forward

The new research, published in Nature, reported that such drugs can significantly restrict tumor growth and spread and reduce the chances of relapse for a broad range of cancers.

inhibiting p110δ in mice significantly increased cancer survival rates across a broad range of tumor types, both solid and haematological cancers. For example, mice in which p110δ was blocked survived breast cancer for almost twice as long as mice with active p110δ. Their cancers also spread significantly less and survival after surgical removal of primary breast cancer tumors was also vastly improved, which has important clinical implications for stopping breast cancer from returning following surgery.

p110δ inhibitors can shift the balance from the cancer becoming immune to body’s defenses towards the body becoming immune to the cancer, by disabling regulatory T cells. This provides a rationale for using these drugs against both solid and blood cancers, possibly alongside cancer vaccines, cell therapies and other treatments that further promote tumor-specific immune responses.

Reference:

Inctivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407–411

Medulloblastoma, a common childhood brain tumor, is classified into 4 subgroups that vary dramatically in terms of the aggressiveness of the disease. For Group 3 and Group 4 tumors,  hardly any characteristic genomic changes that drive tumor growth and would make potential targets for drug development have been identified. To propose a solution for this challenge, some investigators were systematically analyzing all genomic alterations in pediatric brain cancer to discover new targets for treatment.

They discovered, from 137 cases of aggressive patients, that in some of tumor genomes large regions of DNA had been deleted or duplicated or had changed their orientation. These varying structural changes had common consequences in all tumors under investigation: One of two oncogenes called GFI1 and GFI1B, which are not active in healthy brain tissue, is transcribed in these tumors and thus contributes to the development of cancer.

They also noticed that different structural changes had moved the oncogene from a usually inactive environment to a position close to DNA sequences called “enhancers”, which are involved in the activation of genes. In mice, the researchers subsequently proved that activated GFI1B leads to the development of brain cancer, providing evidence that the “hijacked” gene enhancers promote the onset of cancer.

This research directly contribute to the development of better treatments for children with brain cancer. Substances that block the effects of the GFI1 and GFI1B oncogenes are already being tested in clinical trials and might now also be used to slow down the growth of aggressive Group 3 and Group 4 medulloblastomas.

Another team, dedicated to investigating the epigenetic regulation of gene activity, compared patterns of DNA methylation across the whole genome from 42 medulloblastomas with the patterns found in healthy control tissue. As discovered in this study, numerous genes in tumor cells exhibited low levels of methylation compared to healthy counterparts. At the same time, they were transcribed significantly more frequently than in healthy cells.

Reference:

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014; doi:10.1038/nature13379

As we know, there is limited understanding of the molecular biology of nasopharyngeal cancer. To date, no targeted therapy has been established and there is an urgent need for a comprehensive genomic landscape of this disease to guide the development of novel therapies.

In a novel study, scientists analyzed the genomic DNA and proteins of over 100 nasopharyngeal cancer patients in Singapore, and discovered a distinct mutational signature and 9 significantly mutated genes associated with nasopharyngeal cancer, providing rationale for developing novel therapies for this deadly disease.

With the discovery of these previously unrecognized genetic defects in nasopharyngeal cancer, Scientists will explore the detailed molecular mechanisms of these defects in the next phase of research, and evaluate whether some of the genetic defects can be explored in the clinic to effectively treat this disease.

“We wanted to deepen the understanding of the etiology as well biology of nasopharyngeal cancer with the hope for improvements in diagnostics, prognostics and therapy. By completely deciphering all human genes at the single nucleotide level, our current findings provide an important foundation for the study of the molecular basis underlying this malignancy. More importantly, many potential therapeutic drugs have surfaced from our analysis, with some of them already in use for treating other types of tumours. Therefore, the results have the potential to rapidly facilitate the development of novel treatment strategies for nasopharyngeal cancer patients,” said Prof Koeffler.

Reference:

The genomic landscape of nasopharyngeal carcinoma. Nature Genetics 2014;