Abstract
Cancer recurrence remains a great fear for many cancer survivors following their initial, apparently successful, therapy. Despite significant improvement in the overall survival of many types of cancer, metastasis accounts for ~90% of all cancer mortality. There is a growing understanding that future therapeutic practices must accommodate this unmet medical need in preventing metastatic recurrence. Accumulating evidence supports dormant disseminated tumor cells (DTCs) as a source of cancer recurrence and recognizes the need for novel strategies to target these tumor cells. This review presents strategies to target dormant quiescent DTCs that reside at secondary sites. These strategies aim to prevent recurrence by maintaining dormant DTCs at bay, or eradicating them. Various approaches are presented, including: reinforcing the niche where dormant DTCs reside in order to keep dormant DTCs at bay; promoting cell intrinsic mechanisms to induce dormancy; preventing the engagement of dormant DTCs with their supportive niche in order to prevent their reactivation; targeting cell-intrinsic mechanisms mediating long-term survival of dormant DTCs; sensitizing dormant DTCs to chemotherapy treatments; and, inhibiting the immune evasion of dormant DTCs, leading to their demise. Various therapeutic approaches, some of which utilize drugs that are already approved, or have been tested in clinical trials and may be considered for repurposing, will be discussed. In addition, clinical evidence for the presence of dormant DTCs will be reviewed, along with potential prognostic biomarkers to enable the identification and stratification of patients who are at high risk of recurrence, and who could benefit from novel dormant DTCs targeting therapies. Finally, we will address the shortcomings of current trial designs for determining activity against dormant DTCs and provide novel approaches.
Highlights
Recent years have seen great strides in the treatment of primary tumors, as well as in treating overt metastatic tumors
This review will focus on potential strategies, mechanisms and drugs to be considered for targeting quiescent dormant disseminated tumor cells (DTCs) by manipulating their microenvironment and or their cellintrinsic mechanisms
Several restrictive signals have been described in the bone marrow (BM) and lung that maintain DTCs originating from breast, prostate, head and neck squamous carcinoma and multiple myeloma cells in their quiescent state (Figure 1)
Summary
Recent years have seen great strides in the treatment of primary tumors, as well as in treating overt metastatic tumors. Despite significant improvement in the overall survival of many types of cancer due to earlier detection and newer therapies, recurrence years and decades after curative surgery and standard of care chemotherapy and targeted therapy [3,4,5] still looms as the major unmet medical need. Some cancers are more notorious than others for delayed recurrence These highly recurrent tumors include kidney cancer, acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), melanoma, prostate cancer, ovarian cancer, breast cancer and osteosarcoma. Despite major advances in the treatment of primary tumors, almost all cancer-related mortality is due to recurrence and metastasis and many of the most common cancers have a significant propensity for delayed recurrence [28]. While metastasis and recurrence are the main cause of mortality in cancer patients, the mechanisms underlying metastatic recurrence years and decades after initial treatments are just beginning to unravel. Dormant DTCs linger in the body as ticking time bombs and eliminating or keeping such cells at bay may prevent deadly metastatic relapse
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.