Cancer is a multifactorial disease with increasing incidence. There are more than 100 different cancer types, defined by location, cell of origin, and genomic alterations that influence oncogenesis and therapeutic response. This heterogeneity between tumors of different patients and also the heterogeneity within the same patient’s tumor pose an enormous challenge to cancer treatment. In this review, we explore tumor heterogeneity on the longitudinal and the latitudinal axis, reviewing current and future approaches to study this heterogeneity and their potential to support oncologists in tailoring a patient’s treatment regimen. We highlight how the ideal of precision oncology is reaching far beyond the knowledge of genetic variants to inform clinical practice and discuss the technologies and strategies already available to improve our understanding and management of heterogeneity in cancer treatment. We will focus on integrating multi-omics technologies with suitable in vitro models and their proficiency in mimicking endogenous tumor heterogeneity.
Pancreatic cancer is one of the deadliest cancers and remains a major unsolved health problem. While pancreatic ductal adenocarcinoma (PDAC) is associated with driver mutations in only four major genes (KRAS, TP53, SMAD4, and CDKN2A), every tumor differs in its molecular landscape, histology, and prognosis. It is crucial to understand and consider these differences to be able to tailor treatment regimens specific to the vulnerabilities of the individual tumor to enhance patient outcome. This review focuses on the heterogeneity of pancreatic tumor cells and how in addition to genetic alterations, the subsequent dysregulation of multiple signaling cascades at various levels, epigenetic and metabolic factors contribute to the oncogenesis of PDAC and compensate for each other in driving cancer progression if one is tackled by a therapeutic approach. This implicates that besides the need for new combinatorial therapies for PDAC, a personalized approach for treating this highly complex cancer is required. A strategy that combines both a target-based and phenotypic approach to identify an effective treatment, like Reverse Clinical Engineering® using patient-derived organoids, is discussed as a promising way forward in the field of personalized medicine to tackle this deadly disease.
e15524 Background: Biomarker discovery and development are essential for stratifying cancer patients in order to improve treatment outcomes. In colorectal cancer (CRC), mutations in the TGF-β/BMP pathway, especially in the SMAD4 gene have been correlated with decreased overall survival and are suspected to modulate drug sensitivity on the cellular level, hence SMAD4 mutations are worthwile targets for novel targeted therapy aproaches. Methods: In the present study, we uncover the mechanistic role of a loss-of-function mutation in SMAD4 in syngeneic patient-derived organoids (PDOs). CRISPR-engineered SMAD4R361H PDOs were subjected to a comparative drug screening, RNA-Sequencing and multiplex protein profiling analysis (DigiWest®). We have confirmed the response towards MEK inhibition of the initial model in an additional set of 62 PDOs with known mutational status. Results: We show that acquisition of SMAD4 loss-of-function mutations renders PDOs sensitive to MEK-inhibitors. Further, an activation of the TGF-β/BMP signaling pathway, specifically of the BMP branch was observed in SMAD4wt PDOs; indicating that BMP signaling is likely responsible for the resistance towards MEK inhibition. It is plausible that functional loss of SMAD4 and thus loss of BMP signaling renders SMAD4 mutated tumors more sensitive to MEK-inhibitors. By looking at additional genes involved in TGF-β/BMP signaling that are frequently mutated in CRC, we identified the novel gene mutational SFAB-signature ( SMAD4, FBXW7, ARID1A, or BMPR2), when at least one pathogenic mutation is present in these genes. The frequency of SFAB in CRC patient cohort (TCGA, n = 594) was comparable to the frequency of SFAB in our PDOs. For PDOs with SFAB-signature, we found up to 95% and 70% significant positive prediction for cobimetinib and selumetinib, respectively and also up to 70% positive prediction for trametinib. Thus, the SFAB-signature predicts response to MEK inhibition in PDOs with a very high confidence. We further investigated whether the RAS status of CRC PDOs does predict sensitivity to MEK inhibition. The RAS status alone and in combination with SFAB-signature failed to yield better prediction sensitivity to MEK-inhibitors. Conclusions: The present study is a significant step forward to more personalized treatment regimens for CRC patients by early inclusion of MEK-inhibitors. The SFAB-signature should be put to clinical testing as a RAS-independent biomarker for stratification of patients providing a valuable alternative treatment option against CRC, thus ensuring that all patients receive effective and specific therapies as early as possible.
Background: In colorectal cancer (CRC), mutations of genes associated with the TGF-β/BMP signaling pathway, particularly affecting SMAD4, are known to correlate with decreased overall survival and it is assumed that this signaling axis plays a key role in chemoresistance. Methods: Using CRISPR technology on syngeneic patient-derived organoids (PDOs), we investigated the role of a loss-of-function of SMAD4 in sensitivity to MEK-inhibitors. CRISPR-engineered SMAD4R361H PDOs were subjected to drug screening, RNA-Sequencing, and multiplex protein profiling (DigiWest®). Initial observations were validated on an additional set of 62 PDOs with known mutational status. Results: We show that loss-of-function of SMAD4 renders PDOs sensitive to MEK-inhibitors. Multiomics analyses indicate that disruption of the BMP branch within the TGF-β/BMP pathway is the pivotal mechanism of increased drug sensitivity. Further investigation led to the identification of the SFAB-signature (SMAD4, FBXW7, ARID1A, or BMPR2), coherently predicting sensitivity towards MEK-inhibitors, independent of both RAS and BRAF status. Conclusion: We identified a novel mutational signature that reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. This finding poses a significant step towards better-tailored cancer therapies guided by the use of molecular biomarkers.
Pancreatic cancer remains a lethal disease with only 3 - 8% of patients surviving 5 years after initial diagnosis (WHO, 2012). Reasons for this poor situation are advanced and inoperable tumor stages at time of diagnosis and resistance to conventional therapies. One bottleneck in the development of novel therapies is the restricted availability of preclinical models of high clinical relevance. Since the desmoplastic stroma has impact on the progression and treatment of pancreatic cancer, we investigated the attributes of the murine stroma in patient-derived xenografts that completely replaced the human surrounding tissue within a few months after primary transplantation. We elucidated the functionality of murine tumor microenvironment for growth and therapeutic response in a cohort of well-characterized pancreatic cancer (PDAC) PDX. PDX are a valuable tool for the prediction of therapy response, the identification of new biomarkers and therapeutic targets or pancreatic cancer specific pathways. In this study, 57 patient tumors were collected and immediately transplanted into immunodeficient mice. So far, 14 out of 57 samples were established as passageable pancreatic cancer xenografts (PDX). All engrafted PDX are poorly or moderately differentiated adenocarcinomas. Global gene expression analysis and determination of cancer associated mutations revealed K-ras mutations in 13 and additionally p53 mutations in 9 out of 14 PDX. Furthermore, chemosensitivity to standard of care (SoC) drugs was determined by using clinically relevant and optimized schedules and doses. The testing revealed that the response to Gemcitabine (1/10 responder) was moderate within the PDX panel, while the most efficient drug was Abraxane with 5 out of 10 responders. In general, the response profile of all PDX closely reflected patient's situation in the clinic. Cryo- and formalin-preserved tumor tissues of these chemosensitivity studies were investigated for markers of desmoplastic stroma (SPARC, alpha-SMA, FAP and collagen I). Immunohistochemistry and real-time PCR revealed, that even the replacing murine stroma is characterized by a distinct reactivate nature. Semi-quantitative analysis of stromal components showed that the tumor surrounding tissue mass was not significantly reduced due to therapeutic intervention. Though the tumor burden was diminished under SoC, the mRNA expression level of SPARC and FAP was unaffected in corresponding samples of the treatment groups compared to vehicle-treated control. The same effect was found for alpha-SMA and collagen I in immunohistochemically stained specimens. In summary, this study revealed a functional tumor environment of murine origin in patient-derived xenografts of pancreatic cancer and furthermore an apparently inherent resistance of this stromal tissue towards conventional therapy. Thus, targeting the tumor microenvironment should be implicated into clinical decisions. Citation Format: Diana Behrens, Ulrike Pfohl, Britta Büttner, Jens Hoffmann, Wolfgang Walther, Iduna Fichtner. Analysis of murine stromal components in patient-derived xenograft (PDX) models of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4080.
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