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RBM3: a Prognostic and Treatment Predictive Biomarker

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RBM3: a Prognostic and Treatment Predictive Biomarker RBM3: A Prognostic and Treatment Predictive Biomarker Introduction it has also been shown that RBM3 attenu- Cancer is continuously a major health ates stem cell-like properties in prostate problem throughout the world. In 2008, cancer cells6. there were an estimated 12.7 million new cancer cases world-wide, and 7.6 RBM3 monoclonal antibody million deaths that could be attributed to The monoclonal Anti-RBM3 antibody cancer1. Due to a world population with AMAb90655, used in all cases presented an increased life-expectancy, there is no here (available for purchase from Atlas reason to expect a decline in cancer inci- Antibodies, Stockholm, Sweden, atlasan- dence in the near future2. tibodies.com), has shown excellent spe- cificity in Western Blot analysis of human Cancer, though often denoted as a sin- cell lines, and is routinely used for stain- gular disease, is truly a multitude of dis- ing of formalin fixed paraffin embedded eases. This understanding has evolved tissue in IHC. A representative image of over the years, and though common immunohistochemical staining using the knowledge today, many patients are still RBM3 monoclonal antibody AMAb90655 not receiving optimal treatment for their can be seen in Figure 1. disease. For cancer patients to receive a more individualized treatment, there is RBM3 as a prognostic biomarker still a need for new and better ways to After identification of RBM3 as a poten- stratify patients. The classical, pathol- tial prognostic biomarker, RBM3 protein ogy based, prognostic factors such as expression has been analyzed using stage and grade of the tumor are insuf- AMAb90655 in many different patient co- ficient for a correct estimation of patient horts from various forms of cancer. Levels prognosis. Additional information from of RBM3 expression was found to have immunopathology biomarkers promise to a significant connection to patient survival substantially improve this estimation, ul- in breast7, colon8, ovarian9,10, testicular, timately leading to a more individualized urothelial11, and prostate12 cancer as well treatment, thus avoiding both under- and as in malignant melanoma13. over treatment of patients. RBM3 and the Human Protein Atlas The RNA-binding motif protein 3 (RBM3) was recently identified via the Human Figure 1 Protein Atlas (HPA) as a potential oncol- Figure 1 shows representative nuclear staining of ogy biomarker through the differential RBM3 in urothelial bladder cancer, with no RBM3 ex- expression pattern present in several pression (A), intermediate RBM3 expression (B) and high RBM3 expression (C) respectively. cancers investigated as part of the HPA project (proteinatlas.org)3,4. RBM3 is an RNA- and DNA-binding pro- tein, whose function has not been fully elucidated. It has been shown that the protein is expressed as an early event in mild hypothermia, and also in other con- ditions relating to cellular stress, such as glucose deprivation and hypoxia5. During stress, RBM3 is thought to protect the cells by aiding in maintenance of protein synthesis needed for survival5. Recently, Page 1 (4) Urothelial cancer A 1,0 B 1,0 A major clinical problem in urothelial can- cer is the identification of high-risk pa- 0,8 0,8 tients among those diagnosed with non- invasive disease. For patients with stage 0,6 T1 disease (where the tumor has invaded 0,6 connective tissue but not yet muscle), the prognosis is generally good, but nearly 0,4 0,4 one third of these patients will still even- Disease specific survival tually require cystectomy when other 0,2 Five year overall survival 0,2 RBM3 negative; n=67, p<0.001 RBM3 negative; n=78, p<0.001 therapies have failed. The identification of RBM3 intermediate; n=188, p=0.016 RBM3 intermediate; n=215, p=0.035 RBM3 high; n=46 (reference) RBM3 high; n=53 (reference) these patients at an early stage would be 0,0 0,0 a great improvement for patients as well 0 50 100 150 200 250 0 10 20 30 40 50 60 Months from diagnosis as society. Due to high recurrence rates, Months from diagnosis and need for invasive monitoring of the Figure 2 disease, the health care cost per patient Figure 2 shows Kaplan-Meier analysis of cancer-specific (A) and 5-year overall (B) survival of 343 bladder can- cer patients stratified according to RBM3 expression. is higher for urothelial cancer than for any other cancer in the USA11. For patients with muscle-invasive disease, prognos- tic markers that could guide in the choice A 1,0 B 1,0 of treatment and/or treatment intensity would also mean an improvement in pa- tient care. 0,8 0,8 RBM3 has been shown to be a prognostic 0,6 0,6 marker in urothelial cancer, with a signifi- cantly improved survival for patients with 0,4 0,4 Overall survival high levels of RBM3 expression in their Overall survival tumors11 (see Figure 2). This means that 0,2 RBM3 negative; n=33, p=0.005 0,2 RBM3 negative; n=33, p=0.006 analysis of RBM3 expression could be a RBM3 intermediate; n=151, p=0.231 RBM3 positive; n=198 (reference) RBM3 high; n=47 (reference) prognostic factor for better stratification 0,0 of patients, leading to a more individual- 0,0 ized treatment of patients with urothelial 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Months from diagnosis Months from diagnosis cancer. Figure 3 Figure 3 shows Kaplan-Meier analysis of 5-year overall survival of the 231 patients in the cohort diagnosed with Figure 3 shows overall survival of the pa- stage Ta or T1 disease. Patients were stratified according to RBM3 expression, either according to negative, tients in the cohort with Ta (non invasive) intermediate, and high expression (A), or according to negative vs. positive expression (B). and T1 tumors, and the same results can be seen as for the full cohort. For the sub- group of patients with T1 tumors, 5-year overall survival was significantly reduced for patients with tumors not expressing RBM3, indicating that IHC analysis of RBM3 expression may indeed be used to identify stage T1 patients in need of cys- tectomy. The prognostic significance of RBM3 in urothelial cancer has been con- firmed in several independent cohorts. Page 2 (4) Colorectal cancer A 1,0 B 1,0 RBM3 low; n=123, p<0.001 In colorectal cancer, a major clinical prob- RBM3 intermediate; n=60, p=0.064 RBM3 low; n=123, p<0.001 RBM3 high; n=62 (reference) RBM3 high; n=122 (reference) lem is to identify patients in need of adju- 0,8 0,8 vant therapy. The only curative treatment today is surgery, but adjuvant treatment 0,6 0,6 may prolong patient survival, and is rec- ommended for patients with stage III and 0,4 0,4 Overall survival high-risk stage II disease. However, not Overall survival all high-risk stage II patients benefit from 0,2 0,2 adjuvant treatment, thus to categorize these patients is of outmost importance. 0,0 0,0 A biomarker that provides additional in- 0 5 10 15 20 0 5 10 15 20 Years from diagnosis Years from diagnosis formation on risk assessment would be a Figure 4 great step to improve patient care. Figure 4 shows Kaplan-Meier analysis of overall survival of 305 colorectal cancer patients. Patients were strati- fied according to RBM3 expression, either according to low, intermediate or high expression (A), or according to low versus high expression (B). RBM3 has been shown to be a prognostic marker in colorectal cancer in two inde- pendent patient cohorts, with a significant- RBM3 as a treatment predictive in the cisplatin sensitive A2780 cells, they ly improved survival for patients with high biomarker became significantly less sensitive to cis- levels of RBM3 expression in their tumors8 During analysis of RBM3 as a prognos- platin treatment as can be seen in Figure (see Figure 4). This means that analysis of tic biomarker in ovarian cancer, it was 7, where the viability of RBM3-high cells RBM3 expression could be a a prognostic speculated about the potential connection is lower than that of RBM3-low cells. In factor for better stratification of patients, between sensitivity to platinum-based a clinical setting, this finding would corre- leading to more appropriate treatment for therapies and RBM3 expression9. Cis- spond to improved survival for cisplatin- patients with colorectal cancer. When ana- platin treatment is a cornerstone in ovar- treated patients with tumors expressing lyzing patients with stage II disease only, ian cancer treatment and most patients high levels of RBM3 as compared to cis- similar results can be seen as for the full in the cohorts analyzed were thus likely palatin-treated patients with low levels of cohort (Figure 5), indicating that analysis treated with cisplatin. The ovarian can- RBM3 expression in their tumors. of RBM3 expression may be a valuable cer cell lines A2780 and A2780-Cp70 (a tool in deciding whether or not stage II cisplatin resistant cell line derived from colorectal cancer patients should receive A2780) can be used as a model system adjuvant treatment for their disease. for studies related to cisplatin treatment and response. Studies of these two cell It could be concluded that RBM3 is a lines revealed that RBM3 expression (as- prognostic marker that may aid in deter- sessed by Western Blot as well as IHC mining if patients should receive adjuvant analysis) was significantly higher in the treatment, and also the intensity of the cisplatin sensitive A2780 cell line than treatment. in the cisplatin resistant cells (Figure 6). This finding was also confirmed by mRNA 1,0 analysis of RBM3 mRNA levels in the two RBM3 low; n=48, p=0,05 cell lines.
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