Researchers find potential new treatment approach for pancreatic cancer

Dec. 20, 2013 — Scientists from The University of Manchester -- part of Manchester Cancer Research Centre believe they have discovered a new way to make chemotherapy treatment more effective for pancreatic cancer patients.

Pancreatic cancer is an aggressive cancer with poor prognosis and limited treatment options and is highly resistant to chemotherapy and radiotherapy.

But researchers believe they have found an effective strategy for selectively killing pancreatic cancer while sparing healthy cells which could make treatment more effective.

Dr Jason Bruce, from the Physiological Systems and Disease Research Group, who led the research, said: "Pancreatic cancer is one of the most aggressive and deadly cancers. Most patients develop symptoms after the tumour has spread to other organs. To make things worse, pancreatic cancer is highly resistant to chemotherapy and radiotherapy. Clearly a radical new approach to treatment is urgently required. We wanted to understand how the switch in energy supply in cancer cells might help them survive."

The research, published in The Journal of Biological Chemistry this month, found pancreatic cancer cells may have their own specialised energy supply that maintains calcium levels and keeps cancer cells alive.

Maintaining a low concentration of calcium within cells is vital to their survival and this is achieved by calcium pumps on the plasma membrane.

This calcium pump, known as PMCA, is fuelled using ATP -- the key energy currency for many cellular processes.

All cells generate energy from nutrients using two major biochemical energy "factories," mitochondria and glycolysis. Mitochondria generate approximately 90% of the cells' energy in normal healthy cells. However, in pancreatic cancer cells there is a shift towards glycolysis as the major energy source. It is thought that the calcium pump may have its own supply of glycolytic ATP, and it is this fuel supply that gives cancer cells a survival advantage over normal cells.

Scientists used cells taken from human tumours and looked at the effect of blocking each of these two energy sources in turn.

Their study, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), National Institute of Health Research (NIHR) Biomedical Research Centre and AstraZeneca, shows that blocking mitochondrial metabolism had no effect. However, when they blocked glycolysis, they saw a reduced supply of ATP which inhibited the calcium pump, resulting in a toxic calcium overload and ultimately cell death.

Dr Bruce added: "It looks like glycolysis is the key process in providing ATP fuel for the calcium pump in pancreatic cancer cells. Although an important strategy for cell survival, it may also be their major weakness.

"Designing drugs to cut off this supply to the calcium pumps might be an effective strategy for selectively killing cancer cells while sparing normal cells within the pancreas."

Maggie Blanks, CEO of the national charity, the Pancreatic Cancer Research Fund said: "These findings will certainly of great interest to the pancreatic cancer research community and we'd be keen to see how this approach progresses. Finding weaknesses that can be exploited in this highly aggressive cancer is paramount, so we want to congratulate the Manchester team for their discovery."

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Multicenter study underscores need for uniform approach to bladder cancer

Nov. 15, 2013 — New study, involving eight Italian research centres, concluded that an aligned approach to the treatment of advanced bladder cancer is much needed, while confirming previously published results on survival estimates of associated salvage therapies.

According to the lead author, Dr. Francesco Atzori, progress in developing new effective drugs in bladder cancer has been stagnant in the last decades.

"In patients who recur or who are refractory to first-line therapy, response rates and outcomes are grim, and to date, no second-line therapy has been clearly established," he explained.

The authors state that while upfront chemotherapy (CT) confers over 50% response rate, progression free survival and overall survival rates are still dismal. While vinflunine is approved by the EMA for progressive bladder cancer after platinum-based therapy, the US FDA has no approved agents.

In the course of the study, the researchers retrospectively queried all patients receiving 2nd and 3rd line regimens in Italy in the period between 2001 and 2013. The inclusion criteria included failure of one or two prior CT regimens for metastatic disease and no exclusion of specific salvage regiments, including targeted agents. Distribution of treatments and outcome parameters were the primary endpoints.

The authors identified a total of 160 eligible pts across 8 centers nationwide. Median age was 67 years (IQR 39-82), most frequent sites of disease at relapse were: nodes 71% (nodes only 43, 26.9%); lung 30%, bone 26% and liver 20%. Bellmunt Score available in 147 out of 160 patients was 0, 1, 2 and 3 in 63 (43%), 59 (40%), 20 (14%) and 5 (3%) patients respectively.

Regiments used as upfront CT were cisplatin-gemcitabine in 65 patients (41%), carboplatin-G in 50 patients (31%), MVAC in 25 patients (16%), other combination CT in 5 patients (3%) and single-agent CT in 15 patients (9%).

In 2nd line 42 patients (26%) received paclitaxel, 40 (25%) vinflunine, 21 (13%) pazopanib, 10 (6%) MVAC, 47 (29%) other drugs alone or combined.

75 out of 160 patients (47%) received a 3rd line regimen: 19 (25%) paclitaxel, 15 (20%) pazopanib, 11 (15%) MVAC, 30 patients (40%) miscellaneous. Median time-to-relapse to 1st line was 2 months. Overall response rate in 2nd line was 21% (32 out of 160 patients) and 21% in 3rd line (16 out of 75 patients); median progression-free survival was 2,8 and 2 months in 2nd and 3rd line respectively, median overall survival was 16 months and 20 months, in 2nd and 3rd lines respectively. Patients treated with paclitaxel and vinflunine in 2nd line showed a median progression free survival of 2.7 and 3.3 months while overall survival was 13.5 and 13.4 months respectively.

The results of this study will be presented at the European Multidisciplinary Meeting on Urological Cancers, in Marceille, France, on 15-17 November 2013.

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A genome-forward approach to tackling drug-resistant cancers

Sep. 19, 2013 — If you really want to understand why a particular human cancer resists treatment, you have to be able to study that tumor -- really study it -- in a way that just isn't possible in humans. Cancer biologists have been developing a new approach to this challenge, by transplanting human cancers directly from patients to mice whose crippled immune systems will allow those human tissues to grow. According to research published in the Cell Press publication Cell Reports on September 19th, this new approach permits analysis of human cancer in unprecedented detail. The new work shows that those transplanted cancers, known as PDX (for patient-derived xenografts), are very good genomic replicas of the original at every level of analysis.

Overall, the PDX approach promises to speed the development of new drugs along with doctors' ability to make more precise choices about how those drugs are used to treat patients, the researchers say.

"The development of precision pharmacology is clearly the current focus in PDX research," said Matthew Ellis of Washington University in St Louis. "Human testing is hugely expensive, and often the response rates for the patients on experimental drugs are low because the biology of each patient is not well defined. Panels of clinically and genomically annotated PDX can therefore be very valuable for studying drug action and developing predictive biomarkers. Extensive pre- and post-drug sampling can be conducted to study drug effects and drug resistance in a way that would be impossible in the clinical setting."

In the new study, Ellis and his team transplanted drug-resistant human breast cancers into mice and then made very detailed comparisons of those transplanted tumors versus the originals.

The researchers' deep whole-genome analyses showed a high degree of genomic fidelity. In other words, the complex human tumor tissues in the mice looked very much like those in the people they originally came from. While some new mutations did arise after transplantation, those genetic changes rarely had functional significance.

The researchers were surprised to discover that the original and PDX cancers were similar at the cellular level as well. Cancer cells carrying mutations that were relatively rare in the patient were also maintained at lower frequencies in the mice. Likewise, more dominant clones in the original tumor tended to stay dominant in the mice. This suggests that the frequency of genetically distinct tumor cells is in an equilibrium that survives transplantation into mice for reasons that aren't yet clear.

An analysis of multiple estrogen receptor-positive PDX from patients with endocrine therapy-resistant disease shows just how this approach can yield tumor-specific explanations for therapy resistance. Resistant tumors were associated with different kinds of alterations to the estrogen receptor gene ESR1, the researchers found, producing different responses to endocrine therapy.

"The prevalence of ESR1 mutations and gene arrangements in the luminal PDX was a deep surprise to me as I thought these events were rare," Ellis said. "There had been very sporadic reports of ESR1 point mutations in clinical samples over the years, but to find them at high prevalence in the PDX and therefore in a setting where the link to endocrine therapy resistance can be directly studied was, for me, a critical breakthrough in our understanding of this critical problem."

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