Pancreatic cancer is one of the most causes of cancer-related death in the United States. While there has been minimal progress regarding cancer-specific outcomes in recent decades, effective biomarkers are a promising tool that will undoubtedly have an important role in the management of patients with pancreatic cancer.

As reported, a large DNA analysis of people with and without pancreatic cancer has identified several novel genetic markers that reflect increased risk of suffering the highly lethal disease. The discovery of these markers is important in identifying people at risk and in interpreting susceptibility to pancreatic cancer.

 Explore disease-causing gene mutations

Investigators used sequencing technology to examine more than 700,000 sites of the genome known to have single nucleotide polymorphisms (SNPs). They then looked for variants that are likely to be associated with the alteration of gene expression, and found 5 new risk markers, along with 4 risk-associated SNPs identified previously.

Previously approved by the Food and Drug Administration, serum CA-19-9 (carbohydrate antigen 19-9) is utilized for pancreatic cancer as a prognostic marker and as a marker of disease recurrence.

The risks linked to each SNP or marker were largely independent and additive, so that they may have utility in future attempts to identify individuals in the general population at higher risk for pancreatic cancer. The average lifetime risk of pancreatic cancer is 1.5 %.

The long-term goal is to create a “risk stratification tool” that could be used in primary care practice to identify individuals who should undergo screening for pancreatic cancer with tests such as ultrasound or MRI.

Reference:

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nature Genetics, 2014

The number of bladder cancer patients diagnosed in the UK was 10,399 in 2011, with approximately 30 % of patients developing invasive tumours which infiltrate the muscle of the bladder. However, to date ,this common type of bladder cancer remains to be an incurable disease in lack of targeted therapy. Fortunately, scientists at York made a great discovery that could help to improve the treatment of this disease.

Professor Jenny Southgate, in the Department of Biology at York, discovered a extremely aggressive type of muscle-invasive cancer, and initially confirmed that this type of tumour could be cured using drugs that target the epidermal growth factor receptor (EGFR) signalling pathway which controls cell proliferation.

 Another research in France also found specific biomarkers of this tumour sub-type and showed that potential targeted treatment was effective in preclinical models. The multi-disciplinary research, which involved biologists, bioinformaticians, pathologists and clinicians, is published in Science Translational Medicine.

A promising therapeutic target for bladder tumour

Analysis of gene expression of 383 invasive bladder tumours enabled the researchers to identify a extremely aggressive group of tumours, representing around 24 % of bladder invasive tumour cases. The researchers analyzed the molecular changes in this group, which revealed a permanent activation of the EGFR signaling pathway which controls cell proliferation. This signaling pathway, therefore, constitutes a promising therapeutic target.

The genetic expression profile of the tumours was found to be very similar to a particular type of aggressive breast cancer tumours. The identification of a preclinical model of bladder cancers enabled the researchers to test the efficacy of an anti-EGFR drug, which resulted in a significant reduction in tumour progression. The researchers have also found biomarkers allowing the identification of patients who might benefit from this treatment.

Reference:

EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci Transl Med. 2014 Jul 9;6(244):244ra91.

Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Enrique González-Billalabeitia et al. show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, they also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. They further show that superactivation of the prosurvival PI3K–AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53–deficient mouse model of advanced prostate cancer. Their findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer.

The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. They identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer.

Reference:

Vulnerabilities of PTEN–TP53-Deficient Prostate Cancers to Compound PARP–PI3K Inhibition. Cancer Discovery. 2014;4(8):896-904

CD73 generation of immunosuppressive adenosine within the hypoxic tumor microenvironment causes dysregulation of immune cell infiltrates, resulting in tumor progression, metastases, and poor disease outcomes. Therapies targeted toward the adenosinergic pathway, such as antibodies targeting CD73 and CD39, have proven efficacy in mouse tumor models; however, humanized versions are only in preliminary development. In contrast, A2A adenosine receptor antagonists have progressed to late-stage clinical trials in Parkinson disease, yet evidence of their role in oncology is limited. Mark J. Smyth et al. compare the merits and challenges of these therapeutic approaches, identifying tumor indications and combinations that may be fruitful as they progress to the clinic.

High concentrations of immunosuppressive adenosine have been reported in cancers, and adenosine is implicated in the growth of tumors. Release of extracellular ATP in the hypoxic tumor microenvironment is converted to adenosine by CD39 and CD73 ectonucleotidases. CD39 and CD73 are broadly expressed across a number of cell types. Modulation of their distribution can vary dependent on cellular activation and tissue localization. Adenosine enhances polarization of myeloid and T-cell subsets to proangiogenic and immunosuppressive phenotypes, enhancing tumor growth and survival. High adenosine levels affect effector immune cells, NK cells, and CD8+ T cells, responsible for cytotoxic killing of aberrant malignancies due to inhibited expression of molecules that mediate cell death. DC, dendritic cells; IDO, indoleamine 2,3 dioxygenase; TCR, T-cell receptor.

Reference:

Targeting Cancer-Derived Adenosine:New Therapeutic Approaches. Cancer Discovery. 2014;4(8):879-88

Cancer research over the last quarter century has focused almost exclusively on identifying the molecular features of cancer cells based on the idea that genomic changes are in and of themselves the drivers of cancer. Thus, in their original review, Hanahan and Weinberg  attributed the six hallmarks of cancer to genetic alterations within the cancer cell. Similarly, experimental rodent models of cancer focused predominantly on “targets,” that is, the genome of the cell that underwent neoplastic transformation, which afforded a great deal of insight into pathways that are deregulated by genetic aberrations and paved the way for targeted therapeutics.

This focus on the cancer cell genome overshadowed the essential contribution of the tumor microenvironment. The genetic changes occurring in cancer cells were known to affect the microenvironment, but their acquisition was considered to be stochastic. A notable exception was Folkman’s early recognition that vascularity could be the Achilles heel of tumors. Even so, antiangiogenic targets are often conceived of as a means of depriving the autonomous cancer cell of nutrients rather than modifying a necessary cellular partner in neoplastic growth.

As reflected in the updated Hanahan and Weinberg review, the past decade has witnessed increasing acknowledgment that the tumor microenvironment provides the context for carcinogenesis. We now recognize that the key to malignant cells successfully seeding cancer is proper amendment of the soil during neoplastic progression, and that for cancer to evolve from early dysplastic lesions into invasive cancer, malignant cells must continue to modify the tissue in an organ-specific manner to facilitate survival. Thus, the acquisition of mutations, such as activation of oncogenic signaling pathways, by early cancer cells not only promotes cancer cell growth but may also act on the surrounding tissue to recruit and activate stromal cells and reprogram the microenvironment. Therapeutically targeting the tumor microenvironment is now attractive because, compared with the variable routes taken by cells to become cancers, the response of tissues to cancer is relatively consistent. This idea raises the possibility that controlling and eliminating cancer may be more readily achieved indirectly via the tissue microenvironment.

Cancer-associated fibroblasts (CAF) are biologically distinct from resident tissue fibroblasts and are functionally polar opposites. Normal stroma can actively suppress tumor growth, but a shift of programming converts quiescent fibroblasts into CAFs, whose action promotes tumorigenesis. Intriguingly, senescent fibroblasts, which accumulate with age, also display protumorigenic activity. Comparison of the secretory phenotype of CAFs and senescent fibroblasts revealed an overlap in expression of secreted factors referred to as senescence-associated secretory phenotype (SASP) factors. These observations raise the question of how this common secretory phenotype is regulated and whether it provides a therapeutic opportunity.

The new study by Alspach and colleagues in this issue describes a posttranscriptional mechanism mediated by p38MAPK activity on AUF1 to stabilize SASP mRNA species common to both CAFs and senescent fibroblasts . The studies are carefully laid to make a compelling argument in support of their major conclusion that p38MAPK inhibitors, now in clinical trials for other disease states, may be useful in cancer therapy by targeting the stromal cell contribution to cancer growth.

Reference:

Soil Amendments That Slow Cancer Growth. Cancer Discovery. 2014.4(6):637-9

It is a dream for scientists to get the immune system to recognize cancer cells as the enemy and destroy them. And now they are finding that clinical regimens known as immunotherapy can empower a patient’s system to fight the disease like cancer.

With the incredible advances in immunotherapy, oncologists no longer refuse the ‘cure’ word for cancer. It is good news for some patients with metastatic tumors that were almost universally fatal just 5 years ago. They are reinfused with their own T-cells that are genetically programmed, and thereby achieve certain therapeutic effects.

Immunotherapy applied into cancer area

 The concept of immunotherapy dates back to the 19th century. In the 1890s, William Coley tried using heat-killed bacteria to cure cancer. He noticed that some patients seemed to live longer if they developed an infection after their cancer surgery. Over the next 40 years, he injected more than 1,000 patients with bacteria known as Coley’s Toxins—reporting “excellent results” in bone and soft-tissue cancers.

 Scientists make great progress in cancer immunotherapy, especially adapted to cure infiltrated tumor. For all we know, the typical case is that an oncologist infuses lymphoma patients with their own T-cells, re-engineered to produce a chimeric antigen receptor (CAR) or CAR T-cells, once triggered, can eliminate cancer. Unlike antibodies, CAR T-cells may continue to multiply, serving as a “living therapy” throughout a patient’s life.

Take the 2013 Bristol-Myers Squibb study led by Dr. Jedd Wolchok at Memorial Sloan-Kettering Cancer Center. Doctors used a combination of 2 drugs(one approved, the other experimental)in 52 melanoma patients, and found that treatment with both immunotherapy drugs resulted in rapid and deep tumor regressions about 1/3 of the time.

We have reason to believe that Immunotherapy is exciting in terms of its high effectiveness to fight cancer. However it do come with side effects and immune system can be turn on too high. For example, a company temporarily halted its therapeutic cell trials in clinical stage after 2 patients die. But for the most part, adverse reactions reflect autoimmune diseases, where immune cells become hyper-activated and react to normal tissues.

References:

1. Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood. 2014 Jul 21.

2. Modulation of immune responses by immunotherapy in allergic diseases. Curr Opin Pharmacol. 2014 Jul 22;17C:30-37.

A novel study describes, the recognition of unique cancer mutations by an approach appears to be responsible for complete cancer regressions in 2 metastatic melanoma patients treated with a type of immunotherapy called adoptive T-cell therapy. And the finding, published in Clinical Cancer Research, moves one step forward to applying immunotherapy into melanoma.

A researcher remarked, “this study provides the technical solution to identify mutated tumor targets that can stimulate immune responses, which is one of the major bottlenecks in developing a new generation of adoptive T-cell therapy. The two targets identified in this study play important roles in cancer cell proliferation.”

Although up to 72% of the patients with metastatic melanoma experienced tumor regression after adoptive T-cell transfer in a clinical trial. However, some patients remained not to benefit. This is because the targets of T cells remains largely unclear. Thus It is important to establish an  efficient approach for target identification.

Investigators used 2 different approach to identify the tumor targets recognized by the clinically effective T cells. First, they used a conventional cDNA library screening to identify nonmutated targets. Second, they used a tandem minigene library screening to identify mutated targets that cannot be found by the conventional screening.

Using cDNA library screening, the researchers identified 3 novel nonmutated tumor targets, and 4 previously known nonmutated tumor targets. Using tandem minigene library screening, they identified 2 novel mutated tumor targets, KIF2C and POLA2, which play important roles in cell proliferation.

Reference:

Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res. 2014 Jul 1;20(13):3401-10.

A recent study offers the first in vivo evidence that epigenetic alterations alone can cause cancer.As known to us, epigenetic alterations don’t change the DNA sequence but how it expresses. In particular, DNA methylation as an epigenetic switch stably turn off genes, suggesting the potential to cause cancer just as a genetic mutation can.

Direct evidence that DNA methylation drives cancer formation was lacking for a long while. Researchers at Baylor College of Medicine and Texas Children’s Hospital have currently created a mouse model, allowing to validate the effect of DNA methylation on cancer.

Investigators focused on p16, a gene that normally functions to prevent cancer but is commonly methylated in a broad spectrum of human cancers. They devised an approach to engineer DNA methylation specifically to the mouse p16 regulatory region (promoter). As intended, the engineered p16 promoter acted as a ‘methylation magnet’. As the mice reached adulthood, gradually increasing p16 methylation led to a higher incidence of spontaneous cancers, and reduced survival.

This is not only the first in vivo evidence that epigenetic alteration alone can cause cancer, but also has profound implications for future studies, because epigenetic changes are potentially reversible. The findings therefore provide hope for new epigenetic therapies and validate a novel approach for testing them.”

A researcher predicts that this new approach will be widely useful because in addition to p16, there are many other genes and diseases other than cancer that are connected to epigenetics (such as diabetes).As another researcher say, “This opens up the door for a whole new paradigm of how to understand tumorigenesis. If we can identify epigenetic changes that predispose people to cancer, these may actually be treatable or preventable, so this opens up a lot of optimism in new ways to deal with cancer”.

Reference:Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI76507

The treatment of metastatic colorectal cancer has improved markedly during the past 15 years. With the development of irinotecan, oxaliplatin, anti-EGFR antibodies, and anti-VEGF treatment, patients with stage IV colon cancer live on average for 2 years after diagnosis, and 20% of patients can expect to live for 5 years or longer.1 However, of these recent additions to fluorouracil, only oxaliplatin has been useful in the adjuvant setting for patients with stage III colon cancer.

Taieb and colleagues present the latest adjuvant clinical trial testing one of these new agents, cetuximab. The PETACC-8 study was a multi-institutional study in which 2559 patients with stage III colon cancer were randomly assigned to receive either oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) plus cetuximab or FOLFOX4 without cetuximab. The primary endpoint was to assess disease-free survival in the 1602 patients with KRAS wild-type tumours. The investigators reported no difference in disease-free survival or overall survival between the two groups. The study had no major flaws, robust methods, well-balanced groups, and no major design issues. Although CT scanning was not part of the eligibility criteria, 90% of patients received CT scans and investigators recorded no harmful effects.

Unfortunately, these results are similar to the findings of the N0147 trial in the USA, which was a similarly designed study that found no positive effect of the addition of cetuximab to the modified sixth version of FOLFOX (FOLFOX6) in the adjuvant setting. In view of the recent findings of the PRIME and OPUS studies that showed that additional RAS mutations affected outcomes of patients with metastatic disease, a more exhaustive look at RAS mutations might yield better results. However, the results from the subset analysis of N0147 make this highly unlikely. Mismatch repair status could have affected the outcome of this study, but again, lessons from N0147 make this situation unlikely. When taken together, N0147 and PETACC-8 essentially cement the findings of each study.

In view of the effectiveness of anti-EGFR antibody treatment in patients with stage IV colon cancer who do not have mutations of the RAS pathway, the question is why does a strategy that works reasonably well in the metastatic setting have no effect in the adjuvant setting? Two main areas of investigation might give answers to this question. First, the mechanism of development of metastases in colon cancer is probably distinct from the mechanism of worsening metastatic disease. Findings of the study by Taieb and colleagues showed that cetuximab does not affect the metastasis cascade for colon cancer. The beneficial effect in patients with T4N2 disease seen on subset analysis was probably due to the efficacy of this regimen on subclinical metastases as the rapidity of recurrence suggests. Perhaps investigators were lucky with fluorouracil; the drug’s efficacy in the metastatic setting might have nothing to do with its efficacy in the adjuvant setting. An interesting area of study might be to establish what aspects of the metastatic cascade in colon cancer are affected by fluorouracil that cetuximab, bevacizumab, and irinotecan do not.

The second area of investigation includes the heterogeneity of colon cancer. Clinicians divide colon cancer on the basis of molecular genetics. Findings of studies have shown these differences might be apparent from gene expression profiles, but the mechanistic underpinnings and biological function of these transcriptional footprints remain an active area of investigation. Together, these data suggest that molecular changes associated with the metastatic phenotype are not solely defined by genetic mutations and the pathways linked with dissemination are likely to be distinct from those enriched in primary tumours and established metastases.

In view of the paucity of new drugs on the horizon for colon cancer, perhaps we have an opportunity. The recent finding that aspirin might preferentially prevent metastatic disease in PI3K-mutant colon cancers. Efforts within the cooperative groups and major academic programs should be renewed to build on scientific findings regarding the metastatic cascade and attempt to inhibit it by looking at putative inhibitors of specific pathways. The present intergroup adjuvant colon cancer study (CALGB-SWOG 80702) attempts to do this with celecoxib. To find a cure, the present framework of drug development in the adjuvant setting needs to change.

Reference:

The wide gulf between stage III and stage IV colon cancer. The Lancet Oncology. 2014.15(8):785-786

A multicentre, phase 2 trial has shown that selumetinib (an inhibitor of MEK1 and MEK2) provided significantly better progression-free survival and tumour response than did chemotherapy in patients with advanced uveal melanoma.

“Mutations in G-proteins GNAQ and GNA11 are present in 90–95% of patients with metastatic uveal melanoma”, explained senior author Gary Schwartz (Columbia University School of Medicine, Herbert Irving Comprehensive Cancer Center, New York, NY, USA). “These mutations activate a majority of signalling pathways, including MAPK, AKT, and PKC. In laboratory studies, selumetinib completely blocked the MEK pathway, and inhibited growth of uveal melanoma cells in culture.”

To study the efficacy of inhibiting MEK1/2 in uveal melanoma, 101 patients were randomly assigned to receive oral selumetinib or standard chemotherapy. Progression-free survival was significantly longer with selumetinib (15·9 weeks [95% CI 8·4–21·1]) than with chemotherapy (7 weeks [4·3–8·4]; hazard ratio [HR] 0·46 [0·30–0·71], p<0·001); no significant difference in overall survival was seen (11·8 months [95% CI 9·8–15·7] vs 9·1 months [6·1–11·1], respectively; HR 0·66 [0·41–1·06], p=0·09). 49% of patients assigned to selumetinib had tumour regression, whereas no objective responses were reported in the chemotherapy group. 65 (97%) of 67 patients receiving selumetinib had treatment-related adverse events, and 25 (37%) needed dose reductions.

“Targeted therapy is a promising way forward in uveal melanoma”, commented Patrick Ott (Dana-Farber Cancer Institute, Boston, MA, USA). “No systemic treatment was previously shown to work in this disease.”

Lead author Richard Carvajal (Memorial Sloan Kettering Cancer Center, New York, NY, USA) said that future studies include SUMIT (NCT01974752), a phase 3 trial of selumetinib in combination with dacarbazine versus chemotherapy alone, and (based on preclinical data showing that efficacy of MEK inhibition can be enhanced with the addition of AKT or PKC inhibition) a study of trametinib alone or in combination with GSK2141795 and a study of MEK162 and AEB071.

Sapna Patel (MD Anderson Cancer Center, Houston, TX, USA) said, “For the first time in uveal melanoma, we can use targeted therapy to effect tumour response. Targeted therapy with a MEK inhibitor really can potentially be the backbone of new therapy for this tumour.”