DLL3 Delta Like Ligand 3 As Emerging Target In Cancer Therapy

Release Date: 23-Jan-2024

In the relentless pursuit of effective cancer therapies, the need for novel approaches has become increasingly evident. As conventional treatments face limitations, the emergence of Delta-like ligand 3 (DLL3) as a target in the development of cancer therapies marks a significant breakthrough. The anticipation surrounding DLL3 as a therapeutic target reflects the growing recognition of its potential to address unmet needs in the realm of cancer therapeutics.


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Delta-like ligand 3 (DLL3) is a transmembrane protein that plays a crucial role in normal cellular functions. In non-cancerous tissues, DLL3 is primarily involved in embryonic development, where it participates in the regulation of Notch signaling andndash; a fundamental pathway in cellular communication. Notch signaling is pivotal for cell fate determination, tissue patterning, and organogenesis during embryonic development. In the absence of malignancy, DLL3 acts as a mediator of cell differentiation and regulates various cell processes. However, the spotlight on DLL3 has intensified due to its aberrant expression and unique characteristics in certain cancer types.


In cancer, DLL3 takes on a different role, one that has attention for therapeutic targeting. Aberrant expression of DLL3 has been identified in specific cancer types, making it a potential biomarker and therapeutic target. DLL3 is notably overexpressed in cancers of neuroendocrine origin, such as (SCLC), melanoma, glioblastoma multiforme, and other malignancies, providing a distinctive opportunity for intervention.


What makes DLL3 particularly attractive as a therapeutic target is its limited expression in normal tissues, ensuring that targeted therapies aimed at DLL3 are more likely to spare healthy cells. This selectivity is crucial for minimizing off-target effects and improving the overall safety profile for DLL3-targeted therapies.


Therefore, DLL3 inhibition holds promise for the treatment of several cancer types. With small-cell lung cancer being a prominent candidate and the subject of several ongoing studies and clinical trials. SCLC is characterized by aggressive growth, early metastasis, and limited therapeutic options. DLL3 is highly expressed in a significant proportion of SCLC cases, making it a compelling target for the development of therapies aimed at halting the progression of this challenging malignancy.


Several innovative approaches have been employed in the development of DLL3-targeted therapies, each leveraging the unique characteristics of DLL3 to design treatments with enhanced specificity and efficacy. One of them is antibodies, employing bispecific and trispecific antibodies, to target DLL3 and immune cells simultaneously. These have gained traction in cancer therapy in the last 2-3 decades and work by enhancing the immune system’s ability to recognize and eliminate immune cells expressing DLL3.


Rovalpituzumab is a monoclonal antibody designed to target DLL3. It was developed by Stemcentrx (now acquired by AbbVie) but was taken off the pipeline of the companies upon the failure of its conjugated form with tesirine. However, Rovalpituzumab has been frequently used as part of new-generation antibody conjugates with radionuclides, photosensitizers and photoabsorbers in addition to the traditional cytotoxic drugs. However, all these, except antibody-drug conjugates, are still being studied in research studies.


Further, cell therapies, particularly chimeric antigen receptor t-cell and natural killer cell (CAR-T/NK) therapy, have been explored in targeting DLL3-expressing cancer cells. CAR-T and CAR-NK cells are engineered to expressed receptors that specifically recognize and bind to DLL3, triggering an immune response against cancer cells expressing DLL3. This personalized approach shows promise in enhancing the body’s natural defence mechanisms against DLL3-positive tumors.


As research in the field of DLL3-targeted therapies advance, the future landscape holds tremendous potential. Clinical trials evaluating the safety and efficacy of these therapies are underway, with a focus on refining treatment strategies, expanding indications, and improving patient outcomes.


The development of DLL3-targeted therapies not only represents a significant stride in personalized cancer treatment but also underscores the importance of understanding the unique molecular characteristics of cancer cells. As the scientific community continues to unravel the complexities of DLL3 and its role in cancer, the hope is that targeted therapies will provide more effective and less toxic options for patients with DLL3-expressing malignancies.


In conclusion, DLL3 has transitioned from a player in normal cellular functions to a promising target in the quest for effective and targeted cancer therapies. The specific expression patterns of DLL3 in certain cancer types, coupled with the innovative approaches being explored, position DLL3-targeted therapies as a beacon of hope in the evolving landscape of cancer treatment. As research progresses, DLL3-targeted therapies hold the potential to redefine the paradigm of cancer care, offering more precise and personalized interventions for patients facing DLL3-expressing malignancies.

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