Ewing's sarcoma: overcoming the therapeutic plateau

Abstract

The hallmark of Ewing's sarcoma (EWS) is a translocation--t(11;22)(q24;q12)--that most frequently results in the EWS/FLI1 aberrant chimeric gene. Because EWS afflicts young patients, it stands out among the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic chemotherapy regimens produce minimal benefit in patients with metastases at presentation or those with relapsed disease. While the outcomes of chemorefractory EWS patients are generally poor, recent developments have led to the promising use of targeted therapy. Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses. However, targeted therapies in general, and these responders in particular, are faced with the ultimate conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR inhibitor-based regimens with chemotherapy in the upfront setting in newly diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in these patients. Another option is to explore novel targeted multikinase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have experienced a surge in supporting preclinical data. Drugs inhibiting the downstream targets of EWS/FLI1 are also in preclinical development. However, ultimately, the underlying biomarker correlates of resistance and response must be delineated along with ways to overcome them. Novel agents, together with integration of advances in multimodal approaches (including surgery and radiation), as well as offering targeted therapies early in the disease course represent new strategies for confronting the challenges of EWS.

Figure 1. Responses to IGF1R +/- mTOR inhibitor therapy (Kurzrock et al., 2010; Naing et al., 2012; Subbiah et al., 2011b)

Top panel: CT of the thorax in a patient with Ewing’s sarcoma showing a response to an IGF1R antibody (R1507) alone (Kurzrock et al., 2010). Top left panel is a pre-treatment CT scan of the thorax showing metastatic Ewing’s sarcoma in the lung. Top right panel: Six weeks after IGF1R antibody (R1507) therapy, showing regression of tumor of the thorax in this patient. Bottom panel: Bottom left panel shows a pre-treatment CT scan of the thorax in patient with metastatic Ewing’s sarcoma in the lung. Bottom right panel: Six months after IGF1R antibody plus mTOR inhibitor therapy showing continued response(Naing et al., 2012).

Figure 2. Simplified Insulin-like growth factor 1 receptor (IGF1R) and mTORC1 and mTORC2 signaling [Modified from (Subbiah et al., 2011a; Subbiah et al., 2011b)]

Insulin receptor substrate 1 (IRS1) and phosphatidylinositol 3-kinases (PI3K) are activated by insulin and/or IGF1 signaling at the insulin receptor level. PDK1 and Akt are recruited to the plasma membrane by products of PI3K, PIP2, PIP3 (phosphatidylinositol 3,4,5 trisphosphate and phosphatidylinositol 3,4 bisphosphate). After this event there is phosphorylation and activation of Akt by the mTORC2 complex (mTOR + mLST8+ Rictor). This leads to a chain of activation of numerous targets by Akt. The TSC1/2 complex is also phosphorylated in this fashion. By this mechanism inactivation of TSC2’s GAP activity for the small G protein Rheb is initiated. Subsequently, the new mTORC1 complex (mTOR + mLST8+Raptor) is activated by GTP-bound Rheb and phosphorylates proteins like S6K. This starts a negative feedback loop to modulate auto-activity, through a S6K-mediated pathway decrease in the activation of PI3K. IGF1R antibody inhibits IGF1R signaling and rapalogs inhibit mTORC1 short term, and eventually inhibit mTORC 2 with chronic exposure and also suppress EWS/FLI1 which drives tumorigenesis in Ewing’s sarcoma.