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Most of my tweets are about Environment, Public Health, Sicience, Phylosophy and Interesting Ideas at large.

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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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Gm

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.