Innovative Approaches in the Battle Against Cancer Recurrence: Novel Strategies to Combat Dormant Disseminated Tumor Cells

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.

Keywords: cancer recurrence; disseminated tumor cells; immune evasion and clinical trials; metastasis; tumor dormancy; tumor microenvironment.

Figure 1

Keeping dormant DTCs from causing recurrence. The following scheme illustrates the different sites where dormant DTCs reside and potential factors, signaling axis or targets that can be manipulated by the indicated drugs to maintain their long-term quiescence by either reinstating the dormant niche, inducing cell-intrinsic dormancy mechanisms and/or preventing dormant DTCs engagement with their ‘permissive niche’.

Figure 2

Targeting dormant DTCs for eradication. The following scheme illustrates the different strategies and corresponding drugs that we may utilize to eradicate dormant DTCs. These strategies include inhibiting cell-intrinsic mechanisms of dormant DTCs long-term survival, sensitizing dormant DTCs to chemotherapy treatment and/or preventing dormant DTCs immune evasion. Red line denotes inhibition and green arrow denotes activation.

Figure 3

High level clinical trial design. In order to increase the ability to observe clinical impacts of novel dormant DTCs-targeting drugs, novel trial endpoints may be required. We propose an innovative trial design, namely, improving EFS at a later time point, e.g. 6-12 months following the initial EFS at 12 months post-surgery.

Figure 4

Potential trial to avoid late clinical failure through targeting dormant DTCs. The scenario presented here hypothetically addresses potential drugs that will prevent the outbreak of dormant DTCs in the lungs of OS patients. At the first event of relapse, dormant DTCs that are either quiescent and/or indolent are in the background of proliferating metastases. Upon resection and treatment with the drugs that targets dormant DTCs, cells that are not dormant will not be affected by the treatment and thus may lead to secondary recurrence (“early failure) and therefore a clinical benefit may only be evident at a later time point, i.e., following the initial “failure” to achieve a clinical outcome. By resecting the proliferating metastases and continuing the treatment we may avoid the outbreak of the residing dormant DTCs thus preventing “late failure”.