Molecular Mechanisms And Targeted Therapies For Colorectal Cancer

​​​​​This volume gives the latest developments in on the mechanisms of cancer cell resistance to apoptotic stimuli, which eventually result in cancer progression and metastasis. One of the main challenges in cancer research is to develop new therapies to combat resistant tumors. The development of new effective therapies will be dependent on delineating the biochemical, molecular, and genetic mechanisms that regulate tumor cell resistance to cytotoxic drug-induced apoptosis. These mechanisms should reveal gene products that directly regulate resistance in order to develop new drugs that target these resistance factors and such new drugs may either be selective or common to various cancers. If successful, new drugs may not be toxic and may be used effectively in combination with subtoxic conventional drugs to achieve synergy and to reverse tumor cell resistance. The research developments presented in this book can be translated to produce better clinical responses to resistant tumors.

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality, with 1.9 million incidence cases and 0.9 million deaths worldwide. The global number of new CRC cases is predicted to reach 3.2 million in 2040, based on the projection of aging, population growth, and human development. In clinics, despite advances of diagnosis and surgical procedures, 20% of the patients with CRC present with metastasis at the time of diagnosis, caused by residual tumor cells that have spread to distant organs prior to surgery, affecting the patient survival rate. Standard systemic chemotherapy, alternative therapies that target mechanisms involved in cancer progression and metastasis, immunotherapy, and combination therapies are the major CRC-treatment strategies. In the advanced stage of CRC the transforming growth factor-beta (TGF-β) plays an oncogenic role by promoting cancer cell proliferation, cancer cell self-renewal, epithelial-to-mesenchymal transition, invasion, tumor progression, metastatic spread, and immune escape. Furthermore, high levels of TGF-β1 confers poor prognosis and is associated with early recurrence after surgery, resistance to chemo- or immunotherapy, and shorter survival. Based on the body of experimental evidence indicating that TGF-β signaling has the potential to be a good therapeutic target in CRC, several anti-TGF-β drugs have been investigated in cancer clinical trials. Here, we presented a comprehensive collection of manuscripts regarding studies on targeting the TGF-β signaling in CRC to improve patient's prognosis and personalized treatments.

Drug Resistance in Colorectal Cancer: Molecular Mechanisms and Therapeutic Strategies, Volume Eight, summarizes the molecular mechanisms of drug resistance in colorectal cancer, along with the most up-to-date therapeutic strategies available. The book discusses reasons why colorectal tumors become refractory during the progression of the disease, but also explains how drug resistance occurs during chemotherapy. In addition, users will find the current therapeutic strategies used by clinicians in their practice in treating colorectal cancer. The combination of conventional anticancer drugs with chemotherapy-sensitizing agents plays a pivotal role in improving the outcome of colorectal cancer patients, in particular those with drug-resistant cancer cells. From a clinical point-of-view, the content of this book provides clinicians with updated therapeutic strategies for a better choice of drugs for drug-resistant colorectal cancer patients. It will be a valuable source for cancer researchers, oncologists and several members of biomedical field who are dedicated to better treat patients with colorectal cancer. Presents a systemic summary of molecular mechanisms for a quick and in-depth understanding Updates current trends in the field with pioneering information on drug resistance Encompasses both basic and clinical approaches for a better understanding of unsolved problems from a holistic point-of-view

Themen dieses Bandes sind die molekularen Mechanismen der Tumor-Angiogenese, die Suche nach einschlägigen Targets für die Wirkstoffforschung und die Entwicklung von Kombinationstherapien mit bereits existierenden Ansätzen. Die ideale Informationsquelle für Studenten, Ärzte und Forscher in der Pharmaindustrie!

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality. Transforming growth factor beta (TGF-β) signaling has been associated with CRC growth and metastasis due to its involvement in proliferation, epithelial-to-mesenchymal transition (EMT), and angiogenesis. The TGF-β superfamily contains over forty members, including TGF-βs, Nodal, Activin, and bone morphogenetic proteins (BMPs). Three types of TGF-β receptors (TGFβRs) have been identified: types 1, 2, and 3. After ligand binding, TGF-βR2 recruits and phosphorylates TGF-βR1, which, in turn, phosphorylates downstream SMAD (small mother against decapentaplegic) proteins. Phosphorylated SMAD4 translocates into the nucleus, where it activates the transcription of numerous target genes (including SERPINE1, LTBP2, CDKN1A, ARID3B, ATXN1, PTPRK, RAB6A, SMAD7, EHBP1, etc.), acting predominantly as a tumor suppressor gene. Interestingly, alterations in SMAD4 are frequent in metastatic CRC and, together with TGF-βR2 gene mutations, have been reported as late events able to promote CRC progression. The study of the TGF-β pathway in metastatic CRC is challenging because of the great genetic heterogeneity of CRC. However, the increasing availability of targeted and whole-exome DNA sequencing techniques makes it possible to identify genetic mutations in complex, dynamic, and heterogeneous clinical contexts and make correlations with clinical outcomes.

Colorectal cancer has for more than two decades served as the paradigm for the multi-step concept of cancer initiation and progression. Perhaps more than any other organ site, cancer of the colon is extensively characterized at the molecular level. We are now entering a time when molecular classification, rather than histologic classification, of cancer subtypes is driving the development of clinical trials with emerging targeted therapies. The book will focus on the progression from the identification of mutations that drive colorectal cancer initiation and progression to the search for novel therapies to treat the disease.