Modulating the tumor microenvironment to increase radiation responsiveness

Abstract

Radiosensitivity can be influenced both by factors intrinsic and extrinsic to the cancer cell. One of the factors in the tumor microenvironment (TME) extrinsic to the cancer cell that can affect radiosensitivity is oxygenation. Severely hypoxic cells require a 2-3 fold higher dose of radiation to achieve the same level of cell killing as do well-oxygenated cells. Other elements in the microenvironment that may influence tumor radiosensitivity are the response of stromal cells to radiation and the expression of factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 (HIF-1). There are currently several classes of agents that may increase tumor radiosensitivity by modulating the TME. Pre-clinical evidence indicates that inhibition of VEGF may increase local control after radiation. Several mechanisms have been postulated to explain this including radiosensitization of tumor endothelial cells, prevention of the establishment of new vasculature post-radiation, and increased oxygenation secondary to vascular normalization. Agents targeting HIF-1 also increase local control after radiation in pre-clinical models. This may occur via indirect inhibition of VEGF, which is a downstream target of HIF-1, or by VEGF-independent means. When combined with radiation, the EGFR inhibitor cetuximab improves local control and survival in patients with head and neck cancer. Pre-clinical data indicate that EGFR inhibitors can increase the intrinsic radiosensitivity of cancer cells. They can also improve tumor blood flow and oxygenation, which may increase extrinsic radiosensitivity. One of the pathways downstream of EGFR that may contribute to this effect is the PI3K/Akt pathway. Agents that directly inhibit this pathway improve blood flow and increase tumor oxygenation in pre-clinical models. The challenge remains to obtain clinical data from patients showing that modulation of the TME is an important mechanism by which biological agents can radiosensitize tumors and then to utilize this information to optimize therapy.

Figure 1

Signaling pathways that can be inhibited to increase the radiation response of tumors. Activation of growth factor receptors including EGFR leads to upregulation of numerous downstream pathways. One of these, the PI3K/Akt pathway, has been implicated in radioresistance and in the regulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. Inhibition of the PI3K/Akt pathway has been shown to increase the intrinsic radiosensitivity of cancer cells. However, recent evidence suggests that inhibition of the EGFR/PI3K/Akt pathway can also increase the extrinsic radiosensitivity of tumors by altering the tumor microenvironment, perhaps by improving blood flow and tumor oxygenation.

Figure 2

Xenograft blood flow response to nelfinavir treatment. Nude mouse was injected subcutaneously in the flank with SQ20B head and neck cancer cells or A549 lung cancer cells to form xenograft. When tumor reached a size of ~1 cm in diameter, mouse was anesthetized and injected with microbubble contrast agent, then power Doppler ultrasound was performed. Mouse was then started on nelfinavir-containing diet (80 mg/kg/day). Repeat Doppler measurement was performed at day 5. Doppler flow images are shown pre-nelfinavir (A) and at day 5 (B). Details regarding xenograft production and Doppler imaging can be found in Cerniglia et al. and Pore et al.