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Cancer Mechanisms and Therapy
Research Guide
What is Cancer Mechanisms and Therapy?
Cancer Mechanisms and Therapy is the study of molecular drivers like Pim oncogenes, BRAF mutations, MET amplification, and signaling pathways such as MAPK and Stat3 in tumorigenesis, progression, and metastasis, alongside therapeutic strategies including kinase inhibitors like sorafenib, atezolizumab, and regorafenib primarily for hepatocellular carcinoma and other cancers.
This field encompasses 22,724 works examining Pim-1 and Pim-2 kinases in cell survival, phosphorylation, and hematological malignancies. Research highlights mechanisms such as BRAF mutations in human cancers and MET amplification causing gefitinib resistance via ERBB3 signaling. Therapies like sorafenib extend median survival by nearly 3 months in advanced hepatocellular carcinoma compared to placebo.
Topic Hierarchy
Research Sub-Topics
Pim-1 Kinase in Tumorigenesis
This sub-topic examines the role of Pim-1 serine/threonine kinase in promoting cell proliferation and survival during cancer initiation. Researchers study its overexpression in tumors and downstream signaling pathways.
Pim-2 Kinase in Hematological Malignancies
This sub-topic focuses on Pim-2's contributions to leukemia and lymphoma through anti-apoptotic effects and cytokine signaling. Researchers investigate its regulation in blood cancers and prognostic value.
Pim Kinases in Cancer Metastasis
This sub-topic explores how Pim kinases facilitate tumor invasion and metastasis via phosphorylation of migration-related proteins. Researchers analyze interactions with metadherin and epithelial-mesenchymal transition.
Pim Kinase Inhibitors
This sub-topic covers the development and preclinical evaluation of small-molecule inhibitors targeting Pim kinases. Researchers assess selectivity, efficacy in cell survival pathways, and combination therapies.
Phosphorylation by Pim Kinases
This sub-topic investigates substrates phosphorylated by Pim kinases, such as BAD and 4E-BP1, in cell survival and translation control. Researchers map kinase-substrate networks in cancer contexts.
Why It Matters
Targeting specific cancer mechanisms has led to approved therapies that improve survival in advanced hepatocellular carcinoma, a major global cancer burden. Sorafenib increased median survival and time to radiologic progression by nearly 3 months versus placebo in the SHARP trial (Josep M. Llovet et al., 2008, "Sorafenib in Advanced Hepatocellular Carcinoma"). Atezolizumab plus bevacizumab achieved better overall and progression-free survival than sorafenib in unresectable cases (Richard S. Finn et al., 2020, "Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma"). Regorafenib and lenvatinib represent systemic options post-sorafenib failure (Masatoshi Kudo, 2017, "A New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib"). Chemoembolization improves survival in unresectable hepatocellular carcinoma based on systematic review of randomized trials (Josep M. Llovet and Jordi Bruix, 2003). These interventions address resistance mechanisms like MET amplification in lung cancer (Jeffrey A. Engelman et al., 2007).
Reading Guide
Where to Start
"Sorafenib in Advanced Hepatocellular Carcinoma" by Josep M. Llovet et al. (2008) because it provides clinical evidence of kinase inhibition extending survival by nearly 3 months, introducing therapeutic targeting of cancer mechanisms accessibly.
Key Papers Explained
"Mutations of the BRAF gene in human cancer" by Helen Davies et al. (2002) identifies driver mutations in MAPK signaling, which "MAP kinase signalling pathways in cancer" by Amardeep S. Dhillon et al. (2007) expands on mechanistically; "Stat3 as an Oncogene" by Jacqueline Bromberg et al. (1999) links to parallel survival pathways. Therapeutically, "Sorafenib in Advanced Hepatocellular Carcinoma" by Josep M. Llovet et al. (2008) applies multikinase inhibition, advanced by "Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma" by Richard S. Finn et al. (2020) with immunotherapy. "MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling" by Jeffrey A. Engelman et al. (2007) shows resistance mechanisms building on these.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Current frontiers involve sequencing therapies post-sorafenib with regorafenib and lenvatinib in hepatocellular carcinoma, as outlined in "A New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib" by Masatoshi Kudo (2017). No recent preprints or news available.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | The 2007 WHO Classification of Tumours of the Central Nervous ... | 2010 | Digital Access to Scho... | 13.8K | ✓ |
| 2 | Sorafenib in Advanced Hepatocellular Carcinoma | 2008 | New England Journal of... | 12.7K | ✓ |
| 3 | Mutations of the BRAF gene in human cancer | 2002 | Nature | 10.5K | ✓ |
| 4 | Atezolizumab plus Bevacizumab in Unresectable Hepatocellular C... | 2020 | New England Journal of... | 6.7K | ✓ |
| 5 | A New Era of Systemic Therapy for Hepatocellular Carcinoma wit... | 2017 | PubMed | 5.9K | ✕ |
| 6 | Efficacy and safety of sorafenib in patients in the Asia-Pacif... | 2008 | The Lancet Oncology | 5.8K | ✕ |
| 7 | <i>MET</i> Amplification Leads to Gefitinib Resistance in Lung... | 2007 | Science | 4.4K | ✕ |
| 8 | Systematic review of randomized trials for unresectable hepato... | 2003 | Hepatology | 3.0K | ✓ |
| 9 | MAP kinase signalling pathways in cancer | 2007 | Oncogene | 3.0K | ✕ |
| 10 | Stat3 as an Oncogene | 1999 | Cell | 2.8K | ✓ |
Frequently Asked Questions
What role does sorafenib play in hepatocellular carcinoma therapy?
Sorafenib is a kinase inhibitor that extends median survival by nearly 3 months and time to radiologic progression in patients with advanced hepatocellular carcinoma compared to placebo. This was shown in a phase III trial (NCT00105443). It targets mechanisms in cancer progression applicable to broader kinase-driven tumors.
How do BRAF mutations contribute to cancer?
BRAF mutations drive human cancers by activating MAPK signaling pathways essential for cell proliferation and survival. Helen Davies et al. (2002) identified these mutations across various cancer types. They represent a key oncogenic mechanism targeted by inhibitors.
What causes resistance to gefitinib in lung cancer?
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling, bypassing EGFR inhibition. Jeffrey A. Engelman et al. (2007) demonstrated this in a gefitinib-sensitive cell line that acquired resistance. This mechanism informs combination therapies.
How does atezolizumab plus bevacizumab compare to sorafenib?
In unresectable hepatocellular carcinoma, atezolizumab plus bevacizumab improves overall and progression-free survival over sorafenib. Richard S. Finn et al. (2020) reported these outcomes in a phase III trial (NCT03434379). It combines immunotherapy and anti-angiogenesis.
What is the impact of chemoembolization on unresectable hepatocellular carcinoma?
Chemoembolization improves survival in patients with unresectable hepatocellular carcinoma based on systematic review of randomized trials. Josep M. Llovet and Jordi Bruix (2003) confirmed survival benefits from this locoregional therapy. It serves as a standard non-surgical option.
What is Stat3's role in cancer?
Stat3 functions as an oncogene by promoting tumorigenesis through transcriptional activation of survival genes. Jacqueline Bromberg et al. (1999) established this in cellular models. Targeting Stat3 addresses key cancer progression pathways.
Open Research Questions
- ? How can Pim kinase inhibitors be optimized to overcome resistance in hematological malignancies?
- ? What combinations of BRAF and MEK inhibitors best address MAPK pathway reactivation in mutant tumors?
- ? How does MET amplification interact with other ERBB family members beyond ERBB3 in kinase inhibitor resistance?
- ? Which biomarkers predict response to atezolizumab plus bevacizumab versus sorafenib in hepatocellular carcinoma?
- ? What upstream regulators control Stat3 oncogenic activity in solid tumors?
Recent Trends
The field has 22,724 works with growth data unavailable; high-citation therapies like atezolizumab plus bevacizumab (6678 citations, 2020) build on sorafenib (12748 citations, 2008), shifting hepatocellular carcinoma treatment from monotherapy to combinations, while resistance mechanisms like MET amplification (4417 citations, 2007) remain central.
No recent preprints or news reported.
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