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Pathway profiling and rational trial design for studies in advanced stage cervical carcinoma: a review and a
Susy M E Scholl1, Gemma Kenter, Christian Kurzeder
1Département d'Oncologie, Institut Curie, 75005 Paris, France.
Abstract:
Multiple genetic abnormalities will have occurred in advanced cervical cancer and multiple targeting is likely to be needed to control tumor growth. To date, dominant therapeutic targets under scrutiny for cervical cancer treatment have been EGFR pathway and angiogenesis inhibition as well as anti-HPV vaccines. The potentially most effective targets to be blocked may be downstream from the membrane receptor or at the level of the nucleus. Alterations of the pathways involved in DNA repair and in checkpoint activations, as well as the specific site of HPV genome integration, appear worth assessing. For genetic mutational analysis, complete exon sequencing may become the norm in the future but at this stage frequent mutations (that matter) can be verified by PCR analysis. A precise documentation of relevant alterations of a large spectrum of protein biomarkers can be carried out by reverse phase protein array (RPPA) or by multiplex analysis. Clinical decision-making on the drug(s) of choice as a function of the biological alteration will need input from bio-informatics platforms as well as novel statistical designs. Endpoints are yet to be defined such as the loss (or reappearance) of a predictive biomarker. Single or dual targeting needs to be explored first in relevant preclinical animal and in xenograft models prior to clinical deployment.
Insights
Advanced cervical cancer requires multiple genetic targeting strategies. Research suggests focusing on DNA repair, checkpoint activation, and HPV integration sites for effective tumor control.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Advanced cervical cancer presents multiple genetic abnormalities necessitating multifaceted therapeutic strategies.
- Current treatments focus on the EGFR pathway, angiogenesis inhibition, and HPV vaccines.
- Novel targets may lie downstream of membrane receptors or within the nucleus.
Purpose of the Study:
- To explore potential novel therapeutic targets in advanced cervical cancer.
- To assess the significance of DNA repair pathways, checkpoint activations, and HPV genome integration.
- To evaluate advanced methods for genetic and biomarker analysis.
Main Methods:
- Utilizing Polymerase Chain Reaction (PCR) for frequent mutation verification.
- Employing Reverse Phase Protein Array (RPPA) and multiplex analysis for biomarker documentation.
- Considering complete exon sequencing for future genetic analysis.
Main Results:
- Identifying critical genetic alterations in advanced cervical cancer is key.
- Assessing pathways involved in DNA repair and checkpoint activation is crucial.
- Analyzing HPV genome integration sites offers therapeutic potential.
Conclusions:
- Targeting downstream or nuclear pathways, including DNA repair and checkpoint mechanisms, shows promise for cervical cancer treatment.
- Bio-informatics and novel statistical designs are essential for clinical decision-making.
- Preclinical models are vital for evaluating single or dual targeting strategies before clinical application.
