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Microsatellite instability and a defective Heat Shock protein are linked in Colorectal Cancer

A review of the recent Nature paper: 

Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis.

Dorard C, de Thonel A, Collura A, Marisa L, Svrcek M, Lagrange A, ..., Parc Y, Tiret E, Fléjou JF, Gaub MP, Garrido C, Duval A  Nat Med. 2011 Oct; 17(10):1283-9

Microsatellite instability (MSI) is a well-known feature of a subset of colorectal cancer (CRC) that harbors a defective DNA mismatch system. MSI CRC is characterised by an improved prognosis and may not benefit from adjuvant fluorouracil (5FU) therapy in particular stages. Interestingly, this paper provides a possible MSI-related mechanism with possible implications for treatment and stratification.

The authors found that MSI CRCs can be associated to an aberrant splicing of the heat shock protein HSP111, producing an aberrant isoform, namely HSP110DeltaE9. The overexpression of this isoform in CRC cells affects the function of the naïve protein and increases the sensitivity to 5FU. So, if those cells are more sensitive to 5FU, why clinical trials show that MSI may not respond to this drug? The authors say that subjects with MSI-HSP110DeltaE9 (high) represent only a small fraction of the total MSI CRC cases and clinical heterogeneity is present in this group with respect to 5FU response. Interestingly, this aberrant molecule could be considered a natural inhibitor of HSP110, which has been found overexpressed in CRC and other tumors and associated with poor prognosis and metastases.

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Let's immune system help

Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido, 
Vinod P Balachandran, et al. Nature Medicine17 (2011) 


I would like to hilight this paper to our readership, as many of your are involved in the design of clinical trials and selection of potential biomarkers. This report is one of a handful of high impact papers that report the coperative role that inflammatory infiltrate and non cell autonomous effectors play in modulating response to established agents. This study demonstrates an interesting immunological mechanism of Imatininb  that contributes to the antitumor effect in a Gastrointestinal Stromal Tumor (GIST) mouse model. Inflammatory infiltrate is a known finding in GIST specimens (including intratumoral CD8+ Tcells, Treg cells and macrophages). Acording to the authors, Imatinib activates CD8+ T cells and induces Treg cells apoptosis within the tumor. Imatinib is therefore able to reduce the expression of 2,3-dioxygenase (Ido) of tumor cells. Ido enzyme is involved in the catayzation of immunosuppressive metabolites from tryptophan and therefore mediates downstream immunological response. Interestingly Imatininb resistant tumors, generally as a result of a second KIT mutation, restore the overexpression of IDO and combination of Imatinib with CTLA-4 blockade (a well established immunotherapeutic strategy) act synergistically. This insight provides some hints on something we have been suspecting for a long time. It is easy to predict consequences for rational design of combination therapies and strategies to overcome resistance in Imatinib resistant tumors.

Interdisciplinary approach to cancer patients: time to measure the evidences

Why am I publishing this post? Because still a small percentage of patients is treated in Comprehensive Cancer Centers. Although, that is not the only kind of place a patient can receive multidisciplinary care, I assume this is at least partially true. How can we account for the advantages of "personalized" treatment, due to multistep re-evaluation of the case?

Several reports tell us interdisciplinary approach may save months to our patients, especially the most challenging ones (such as pancreatic cancer), or during the most delicate phase of their disease (unclear therapeutic options, multifocal or metastatic disease). If a treatment gives you a 10% better event free survival, wouldn't you feel obliged to test it and eventually offer it to every one?

http://www.ncbi.nlm.nih.gov/pubmed/21941491

Case Rep Oncol. 2011 May;4(2):413-419. Epub 2011 Aug 24.

Long-Term Relapse-Free Survival by Interdisciplinary Collaboration in a Patient with Metastatic Pancreatic Cancer (UICC IV).

Roehrig S, Wein A, Albrecht H, Maennlein G, Wolff K, Muskoski D, Amann K, Janka R, Hohenberger W, Hahn EG, Siebler J, Neurath MF, Boxberger F.

Source

Department of Internal Medicine 1, University of Erlangen, Erlangen, Witten, Germany.

Abstract

INTRODUCTION:

The prognostic outlook for patients suffering from pancreatic cancer is generally poor. Particularly in cases of advanced and metastatic disease, long-term relapse-free survival may be achieved only in a few cases.

CASE REPORT:

A 45-year-old patient presented with metastatic pancreatic cancer. Liver metastases had been intra-operatively confirmed by histology. Prior to initiating treatment, a portacath was surgically implanted. Subsequently, the patient received a weekly dose of 1,000 mg/m(2) gemcitabine combined with 2,000 mg/m(2) high-dose 5-fluorouracil as a 24-hour infusion for palliative treatment. As the patient was suffering from a stenosis of the ductus hepaticus communis, an endoprosthesis was primarily implanted. After 18 applications of chemotherapy during which only low toxic side effects such as nausea, vomiting and alopecia (NCI-CTC grade 1) presented, a partial remission of the primary tumor was observed. In the course of chemotherapy treatment, the carbohydrate antigen 19-9 tumor marker value normalized. Thus, the interdisciplinary tumor board of the University of Erlangen decided to perform a laparoscopy to evaluate the status of liver metastases after palliative chemotherapy treatment. Subsequently, the primary tumor could be completely resected (pT2, pN0, pM0, L0, V0, G2, R0); liver metastases were not observed. Eight years after the initial diagnosis, the patient is relapse-free, professionally fully integrated and presents with an excellent performance status.

CONCLUSION:

Patients suffering from metastatic pancreatic cancer may benefit from treatment combinations with palliative intent. In singular cases, patients may even have a curative treatment option, provided a close interdisciplinary collaboration exists.

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Expanding cancer boundaries, Immune response is not enough.

Pancreatic Adenocarcinoma is characterized by an immune reaction that is immunosuppressive since the earliest stages of tumor development (Clarck et al., 2007). In a recent article in Science the group leaded by Vonderheide at UPENN investigated the effect of re-activation of the immune response against cancer by the use of CD40 in addition to Gemcitabine in a small group of unresectable pancreatic cancer patients. Encouraging results showed partial response in a number of patients enrolled in this study. 

At first sight this confirm the idea that immune therapies should be increasingly tested in controlled studies and eventually become one of the foundation of combination therapies. However when the looked for effective T cell response against tumor in patients and in a Kras and p53 mutated mouse model of pancreatic cancer they didn't observe what they were expecting. What they found instead is a macrophage activation that rapid infiltrated tumor and facilitated depletion of stroma suggesting the immune surveillance was not induced by T cells. This paper follows the revolutionary findings of Tuveson's group (Olive et al, 2009) on the relevance of stroma directed treatments in facilitating drug delivery and anti-tumor efficacy of chemotherapy.

It is exciting to see things coming together in a more comprehensive view of events than we could only imagine a few years ago: novel compounds selectively acting on cancer molecular targets, immune response and microenvironment unveil unanticipated anticancer mechanisms and synergies.

Good News About a Very Bad Cancer - ScienceNOW

From sciencemag.com

Pancreatic cancer is relentless and typically kills patients within a few months. Now scientists report that a treatment that fires up certain immune cells extends the lives of pancreatic cancer patients by more than 30%. Although the recipients survived for only about an extra 2 months, cancer researchers are enthusiastic about the results.

The statistics on pancreatic cancer are dismal. Only about 5% of patients with pancreatic ductal adenocarcinoma (PDA), the most common form of the disease, are alive 5 years after diagnosis. And the odds of beating pancreatic cancer haven't improved much in the past 35 years, notes surgeon and cancer researcher Jason Fleming of MD Anderson Cancer Center in Houston, Texas. "We are really at square one with survival," he says.

One of pancreatic cancer's dirty tricks involves co-opting white blood cells called leukocytes. Instead of attacking, these turncoats infiltrate the cancer and "essentially wall it off from the antitumor effects of the immune system," says tumor immunologist Robert Vonderheide of the University of Pennsylvania's Abramson Cancer Center. Vonderheide and colleagues wondered whether they could turn the immune system against the cancer by triggering CD40, a receptor protein carried by several kinds of defensive cells. Activating CD40 is usually necessary for immune cells to take on tumors.

The researchers dosed 21 PDA patients with the standard chemotherapy drug gemcitabine and an antibody that flips on CD40. Computed tomography scans showed that pancreatic tumors dwindled or stabilized in 15 of the subjects. In some of the recipients, the treatment also shrank metastatic tumors, or colonies from the original cancer that had sprouted in other parts of the body. Historically, PDA patients who receive gemcitabine survive about 5.7 months. But as the researchers report online today in Science, patients in the experimental group lived for 7.4 months.

To determine how the treatment curbed tumor growth, the researchers tested genetically engineered mice that develop PDA. The combination of gemcitabine and a rodent version of the CD40-activating antibody—and even the mouse antibody alone—reduced tumors in about 30% of the animals. The researchers expected that activating CD40 would provoke a counterattack by the immune cells known as T cells. But to their surprise, they found that the antibody worked even in mice that lack these cells. Instead, the attackers were macrophages, a more general kind of defensive cell whose jobs include munching bacterial invaders and helping to heal injured tissue. Macrophages were able to squirm through the white blood cell blockade and start killing the tumor cells.

"These are promising results that need to be expanded and tested further in larger studies," says Vonderheide. One question to investigate, he says, is whether other combinations of treatments boost the activator's killing power, such as pairing it with a vaccine that incites T cells to attack the tumor.

Cancer experts are impressed. "It's a great article," says Fleming. "It's definitely a huge step forward," adds cancer biologist Dafna Bar-Sagi of the New York University School of Medicine in New York City. Stretching survival by less than 2 months might not seem like a big deal, but given the poor prognosis for most patients, "these are significant numbers," says molecular biologist Jonathan Brody of Thomas Jefferson University in Philadelphia, Pennsylvania. All three researchers, who were not involved in the study, agree that the results highlight the importance of designing treatments that focus not just on tumor cells but also on the neighboring tissue that helps them survive and grow. "We need to be targeting those cells," Brody says.

Malaria drug slows pancreatic cancer growth in mouse models - 2011 Press Releases - Dana-Farber Cancer Institute

Malaria drug slows pancreatic cancer growth in mouse models - 2011 Press Releases - Dana-Farber Cancer Institute

Dana-Farber Cancer Institute scientists report that they have shrunk or slowed the growth of notoriously resistant pancreatic tumors in mice, using a drug routinely prescribed for malaria and rheumatoid arthritis.

The pre-clinical results, which will appear in the April issue of the journal Genes & Development and is currently published on its website, have already prompted the opening of a small clinical trial in patients with advanced pancreatic cancer, one of the deadliest and hardest-to-treat forms of cancer, said the investigators, led byAlec Kimmelman, MD, PhD, a radiation oncologist at Dana-Farber.

"We are seeing robust and impressive responses in pancreatic cancer mouse models," said Kimmelman, whose laboratory specializes in studies of pancreatic cancer, the fourth-leading cause of cancer death in the United States. The oral drug, hydroxychloroquine, is inexpensive, widely available, and causes relatively mild side effects, he said. A second, planned clinical trial will combine the drug with radiation.

"While these findings are indeed exciting and a cause for optimism, one needs to be mindful that so far the effects, while impressive, have only been shown in mice," said Ronald DePinho, MD, director of the Belfer Institute for Applied Cancer Science at Dana-Farber. "I eagerly await to see how the human studies will progress."

A new treatment avenue would be extremely welcome in pancreatic cancer. The National Cancer Institute estimates that 43,140 people were diagnosed in 2010 and 36,800 died. Despite some recent gains with targeted molecular agents and combination regimens, only about six percent of patients live five years, and the median survival is less than six months.

Hydroxychloroquine is a form of the drug chloroquine, which is used to prevent and treat malaria and also prescribed for autoimmune diseases, including lupus and rheumatoid arthritis. These compounds have recently stirred much interest in cancer research, because they inhibit a process called autophagy (from the Greek for "self-eating") that is elevated in cancer cells.

Autophagy is present in normal cells as well, but at a much lower level. The process enables cells to break down and eliminate proteins, such as damaged cell membranes and worn-out organelles like mitochondria. But it is also a survival strategy. When nutrients are scarce, cells can digest and feed on their own non-critical proteins to avoid starvation.

Cancer cells also use autophagy to outwit chemotherapy treatment. Research has shown that cancer cells can activate this process in response to a variety of cancer treatments, allowing them to survive during the stress of therapy. But, as Kimmelman noted, autophagy can also be a cell-death mechanism. Cancer researchers are intensely studying - and debating - how to manipulate autophagy as a potential method to slow tumors' growth or make them more sensitive to other therapies.

In their research reported in Genes & Development, Kimmelman and colleagues were stunned to find that autophagy was turned on at all times in pancreatic cancer cell lines — not just under conditions of stress, treatment or starvation.

"This was a big surprise," he said. "These cells weren't deprived of nutrients; they were swimming in all the nutrients they could ever want."

This suggested that for some unknown reason, pancreas tumors are highly dependent on autophagy, and therefore potentially uniquely good candidates for autophagy-inhibiting treatment.

In their next experiments, the team administered chloroquine to several different pancreatic cancer cell cultures, and also tested its effects in three types of mouse models. In the laboratory cultures, they reported, the drug "markedly decreased" the growth of the tumor cells, showing that the cells were heavily dependent on autophagy to for continued growth.

In vivo testing involved three types of mouse models: human pancreatic cancer cells placed under the rodents' skin (xenografts); human cells injected into the animals' pancreases (orthotopic transplants); and a genetic model (mice bioengineered to develop native pancreatic tumors).

The response to chloroquine was "profound" in the xenograft models, Kimmelman said: all eight untreated mice died of their cancer within 140 days, while only one of eight treated mice had died by 180 days.

The drug's effects were less dramatic but still impressive in the orthotopic and genetic mouse models, the researchers said. The tumors that developed in the genetically pancreatic cancer-prone mice were, like their equivalent in human patients, extremely resistant to all treatments. Among other properties, these tumors were embedded in tough, fibrous tissue that is difficult for drugs to penetrate.

Nevertheless, the scientists reported that chloroquine treatment as a single agent increased the rodents' survival by 27 days compared with untreated control mice. This is encouraging, Kimmelman commented, because even the newest targeted drugs aimed at pancreatic cancer "don't have much effect in this genetic mouse model."

The Dana-Farber trial of hydroxychloroquine, led by Kimmelman and oncologist Brian Wolpin, MD, is designed to enroll 36 pancreatic cancer patients in whom first- or second-line treatments have failed. The drug is taken in pill form twice a day. Results won't become available for at least a year, said Kimmelman.

Kimmelman said the next step will be to investigate the combination of hydroxychloroquine with radiation in patients with operable pancreatic cancer.

"This is a very interesting and promising approach, attacking the Achilles' heel in pancreatic cancer's defenses," commented Robert Mayer, MD, of Dana-Farber's Center for Gastrointestinal Oncology. "But it's too early to say whether hydroxychloroquine should be added to chemotherapy, and what the risks and benefits might be, so we want to examine it in a clinical trial."

Kimmelman's lab is also investigating other forms of cancer that might be good candidates for inhibition of autophagy by the drug. He said that their work, as well as recent findings from other labs, suggests that those cancers may be ones that are primarily driven by the KRAS oncogene — as nearly all pancreatic tumors are.

Kimmelman, who also is an assistant professor of radiation oncology at Harvard Medical School, is the senior author of the publication. First author is Shenghong Yang, PhD, a member of the Kimmelman lab. Other authors are from Dana-Farber, Massachusetts General Hospital, Harvard Medical School, Boston University, and scientists from Italy and Germany.

Pancreatic cancers require autophagy for tumor growth

Yang S, Wang X*, Contino G*, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell'antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC.

1. ¹Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
2. ²Cancer Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA;
3. ³Division of General Surgery, European Institute of Oncology, University of Milan, 20141 Milan, Italy;
4. ⁴Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA;
5. ⁵Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
6. ⁶Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 021145, USA;
7. ⁷Department of Pathology, Harvard Medical School, Boston, Massachusetts 021145, USA;
8. ⁸Department of Pathology, San Raffaele del Monte Tabor Scientific Institute, 20132 Milan, Italy;
9. ⁹Helmholtz-Zentrum and Technische Universität München, D-81377 München, Germany;
10. ¹⁰Division of Molecular Oncology, San Raffaele del Monte Tabor Scientific Institute, 20132 Milan, Italy
    11 These authors contributed equally to this work.

Abstract

Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.

Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers

From Science

1. David T. Ting¹,*, 
2. Doron Lipson²,*, 
3. Suchismita Paul¹, 
4. Brian W. Brannigan¹ , 
5. Sara Akhavanfard¹, 
6. Erik J. Coffman¹,
7. Gianmarco Contino¹, 
8. Vikram Deshpande¹, 
9. A. John Iafrate¹, 
10. Stan Letovsky², 
11. Miguel N. Rivera¹, 
12. Nabeel Bardeesy¹,
13. Shyamala Maheswaran¹ and 
14. Daniel A. Haber¹,³,^†

Satellite repeats in heterochromatin are transcribed into noncoding RNAs that have been linked to gene silencing and maintenance of chromosomal integrity. Using digital gene expression analysis, we show that these transcripts are greatly overexpressed in mouse and human epithelial cancers. In 8 of 10 mouse pancreatic ductal adenocarcinomas (PDAC), pericentromeric satellites accounted for a mean 12% (range 1 to 50%) of all cellular transcripts, a mean 40-fold increase over normal tissue. In 15/15 human PDACs, alpha satellite transcripts were most abundant and HSATII transcripts were highly specific for cancer. Similar patterns were observed in cancers of lung, kidney, ovary, colon, and prostate. Derepression of satellite transcripts correlated with overexpression of the LINE-1 retrotransposon and with aberrant expression of neuroendocrine-associated genes proximal to LINE-1 insertions. The overexpression of satellite transcripts in cancer may reflect global alterations in heterochromatin silencing and could potentially be useful as a biomarker for cancer detection.