Sensitization Strategies in Cancer Treatment

Dear Colleauges,

Due to high mortality rates and increasing incidence, cancer research efforts should focus on delineating the molecular basis of tumor resistance to current therapies, which will aid in designing novel strategies or improving the existing ones. Induction of apoptosis is the favored mode of action of most anti-neoplastic chemotherapeutics to eradicate tumors. To avoid apoptosis, tumors assume various mechanisms. For instance, natural apoptosis inhibitors, such as anti-apoptotic Bcl-2 and Inhibitors of Apoptosis (IAP) family members employ different mechanisms to protect tumors against apoptosis induced by anti-cancer agents. Drug-resistance is additionally strengthened by the appearance of the multi-drug resistance (MDR) phenotype following initial chemotherapy administration. 

As dysregulated expression of anti-apoptotic factors contributes to MDR phenotype, drug-resistant tumors may also develop cross-resistance to immune system.  The development of such cross-resistance proposes that drugs and immune- based treatment approaches utilize a common apoptotic machinery. Selective outgrowth of resistant tumors will eventually lead to patients’ demise. Application of high dose chemotherapy and/or combination chemotherapy is restricted due to presence of redundant resistance mechanisms, changes in drugs’ pharmacokinetics, and undesired adverse clinical toxicities.  Ample evidence shows non-toxic agents that interfere with the function of MDR pumps or adversely modulate the cell survival signaling pathways leading to alterations in the expression profile of apoptosis-associated gene products can lead to the generation of a proapoptotic tumor milieu, and can be efficiently used combined with chemo- or immuno-therapy in the clinical treatment of resistant/relapsed tumors.

Despite recent advances in modern clinical oncology (e.g., CAR T cell redirected immunotherapy, immune checkpoint blockade, targeted therapy, etc.) it has become more evident that research and clinical endeavors should focus on determination of cell survival signaling pathways or their apoptosis-resistant down-stream targets tempered by sensitizing agents that avert the resistance of refractory tumors.  Accordingly, the two-signal (functional complementation) model is proposed; short term exposure of tumors to a non-toxic sensitizing agent (e.g., drugs, cytokines) via interference with survival pathways modifies the expression profile of apoptosis-resistance factors, skews the balance towards a proapoptotic phenotype, and remove the inhibitory block in the apoptotic pathway (signal I). Consequently, apoptosis threshold is reduced, thus, tumors become sensitized to the cytotoxic signals delivered by the second agent (e.g., immune effector cells (CTLs, NK cells), biological response modifiers, immunotherapy, chemotherapy) (signal II). Successful application of sensitization approach will substantially reduce (or eliminate) toxic side effects and much lower doses of cytotoxic agents will be required to achieve synergistic apoptosis.

Corroborated by numerous preclinical studies, the functional complementation model confirms that therapeutic agents, possess the ability to directly induce apoptosis, and to modify the gene expression profile and reduce apoptosis threshold, thus, overcoming the acquired or inherent apoptosis-resistance phenotype of refractory/relapsed tumors.

This Special Issue will highlight the power of tumor sensitization to apoptosis, covering both basic and (pre)clinical aspects that advance our understanding and provide rational molecular basis for its utilization in clinical oncology.

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