Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition

Goldman, Aaron; Majumder, Biswanath; Dhawan, Andrew; Ravi, Sudharshan; Goldman, David; Kohandel, Mohammad; Majumder, Pradip K.; Sengupta, Shiladitya

doi:10.1038/ncomms7139

Cited by 240 publications

(316 citation statements)

References 46 publications

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“…Increases in drug levels result in more efficient killing of CCs, CSCs, and ICCs (57,58). Higher oxygen concentrations accelerate the proliferation rates of CCs and the activity of immune cells, whereas hypoxia favors CSC and ICC proliferation (33,34,61). An increase in immune response results in more efficient killing of all cancer cells (53).…”

Section: Dose Scheduling and Time For Tumor Relapse Determine Treatmentmentioning

confidence: 99%

“…The model also accounts for the delivery and cell killing potential of chemotherapy based on the dose and schedule, and for transformations among CCs, CSCs, and ICCs (33). Specifically, as shown in Fig.…”

Section: Significancementioning

confidence: 99%

“…To this end, we have developed a mathematical model for tumor growth that accounts for three different phenotypes of cancer cells-nonstem cancer cells (CCs), CSCs (which are more resistant to drugs, hypoxia, and the immune system), and CCs that are induced by chemotherapy to acquire a more stem-like phenotype, which we refer to as treatment-induced cancer cells (ICCs) (33), as well as immune cells [natural killer (NK) cells, CD8 + T cells, and Tregs], tumor vasculature, and their interactions (Fig. 1).…”

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confidence: 99%

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Role of vascular normalization in benefit from metronomic chemotherapy

Mpekris

Baish

Stylianopoulos

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

119

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Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.thrompospondin-1 | tumor perfusion | oxygenation | immune response | drug delivery

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Section: Dose Scheduling and Time For Tumor Relapse Determine Treatmentmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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Role of vascular normalization in benefit from metronomic chemotherapy

Mpekris

Baish

Stylianopoulos

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

148

119

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“…This heterogeneity can be caused by intrinsic (clonal) or extrinsic (microenvironmental) factors. Next to this, expression of CSC markers might be regulated or influenced by treatments (42)(43)(44)(45). Nevertheless, finding new markers that reliably identify cells with stem cell functionality is essential to break through one of the major barriers for CSC research.…”

Section: Therapy Resistance Of Cscsmentioning

confidence: 99%

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Lenos¹,

Vermeulen²

2016

Ann. Transl. Med.

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A population of stem-like cells in tumors, the so-called cancer stem cells (CSCs), are being held responsible for therapy resistance and tumor recurrence. In analogy with normal stem cells, CSCs possess the capacity of long term self-renewal and multilineage differentiation. CSCs are believed to be more resistant to various therapies compared to their differentiated offspring and therefore the cause of tumor relapse. Markers for CSCs have been identified using xenograft transplantation assays and lineage tracing in mouse models, however the specificity and validity of many of these markers is under debate. Recently, low proteasome activity has been postulated as a novel CSC marker. In several solid malignancies a small subset of low proteasomal activity cells with CSC characteristics were identified, suggesting that proteasomal activity might be a functional marker for CSCs. In this perspective, we will discuss a recent study by Munakata et al., describing a population of colorectal cancer cells with CSC properties, characterized by low proteasome activity and treatment resistance. We will put this finding in a broader view by discussing the challenges and issues inherent with CSC identification, as well as some emerging insights in the CSC concept.

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“…Although the current dogma underlying resistance is based on the Darwinian selection of mutations acquired over time under chemotherapy pressure, emerging evidence indicates that anticancer drugs can be rendered ineffective early on by intrinsic or adaptive resistance as a function of tumor heterogeneity (2)(3)(4). For example, response rates to first-line chemotherapy treatments in metastatic breast cancer patients range from a dismal 30% to 70%, and patients with disease progression need to be switched to a different drug (5).…”

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confidence: 99%

Reporter nanoparticle that monitors its anticancer efficacy in real time

Kulkarni

Rao

Natarajan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.T he failure of anticancer therapy is a major cause of mortality (1). Although the current dogma underlying resistance is based on the Darwinian selection of mutations acquired over time under chemotherapy pressure, emerging evidence indicates that anticancer drugs can be rendered ineffective early on by intrinsic or adaptive resistance as a function of tumor heterogeneity (2-4). For example, response rates to first-line chemotherapy treatments in metastatic breast cancer patients range from a dismal 30% to 70%, and patients with disease progression need to be switched to a different drug (5). Similarly, about 40-60% of patients with a wild-type KRAS do not respond to cetuximab (6). The ability to detect early whether a treatment is working or not and to switch, if necessary, to a regimen that is effective can have a significant effect on the outcome as well as quality of life (7,8).Currently, tumor response to therapy is determined using techniques for direct anatomical measurements, such as computed tomography (CT) and magnetic resonance imaging, or indirectly using positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) to quantify metabolic activity. However, these techniques lack the sensitivity or specificity to enable very early response assessment, and often, clinicopathological and metabolic readouts can be discordant (5, 9, 10). In the case of immunotherapy, for example, a productive immune response (T cell infiltration) and the unimpeded growth of the tumor will both be manifest as progression on the conventional ...

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Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition

Cited by 240 publications

References 46 publications

Role of vascular normalization in benefit from metronomic chemotherapy

Role of vascular normalization in benefit from metronomic chemotherapy

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Reporter nanoparticle that monitors its anticancer efficacy in real time

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