PG11047 showed an activity pattern consistent with cytostasis against the cell lines of the PPTP in vitro
panel. The Ewing sarcoma cell lines appearing somewhat more sensitive and the neuroblastoma cell lines somewhat less sensitive than the remaining cell lines studied. The cytostatic pattern of response observed for the PPTP cell lines is consistent with that recently described for breast cancer, colon cancer, and lung cancer cell lines [10
]. There was a wide concentration range over which the PG11047 half-maximal effect was observed, ranging from less than 10 nM to greater than 1 μM. The three most sensitive cell lines with EC50
values less than 10 nM included two of the four Ewing sarcoma cell lines evaluated as well as an ALL cell line. This exquisite level of sensitivity is not observed in most adult cancer cell lines [1
], but has been noted for select lymphoma cell lines (L. Marton, personal communication). The cellular basis for this high sensitivity has not been identified.
The in vivo
antitumor activity observed for PG11047 against the PPTP childhood cancer models consisted of regression in a single ependymoma xenograft and tumor growth inhibition in selected other xenografts. The degree of tumor growth inhibition was modest, with a single xenograft showing more than a two-fold increase in time to event. Tumor growth inhibition is also described for adult cancer xenografts [10
]. The ependymoma xenograft for which a regression was observed grows slowly, which resulted in there not being a significant difference between the treated and control groups in EFS distribution. Because of this, further testing is required to define the effectiveness for PG11047 for this and other ependymoma xenografts.
There has been substantial interest in the role of inhibitors of polyamine synthesis for neuroblastoma [26
-amplified neuroblastoma shows coordinate deregulation of multiple polyamine enzymes, including ODC, resulting in enhanced polyamine biosynthesis [15
]. Further supporting a role for the polyamine pathway in neuroblastoma, DFMO treatment blocks the proliferative response of MYCN
-amplified neuroblastoma, and when started at birth delays the onset of tumor development in neuroblastoma-prone genetically engineered mice [15
]. Delaying DFMO treatment of genetically engineered mice until after tumor onset produces a small, but significant, extension in the time to tumor progression and death [15
]. The combination of DFMO plus standard chemotherapy agents extends survival beyond that achieved with chemotherapy alone [15
]. There are similarities between the activity of DFMO that has been described for neuroblastoma and that described in this report for PG11047. Both agents induce a cytostatic response associated with cell cycle arrest [11
], and the in vivo
activity of each agent is modest when treatment is initiated after tumor onset [15
]. Transitioning the strategy of polyamine depletion into an effective treatment for neuroblastoma will require the identification of combination therapies that selectively deprive cancer cells of major compensatory pathways, leading to cytotoxic activity with a favorable therapeutic window [26
PG11047 is under clinical evaluation in adults with cancer. The agent has generally been well tolerated [2
]. It is currently in a phase 1b trial (Clinical Trial Identifier: NCT00705874) in which it is given in combination with one of seven different approved drugs, including conventional cytotoxic agents (e.g., cisplatin and gemicitabine) and molecular targeted agents (e.g., sunitinib, bevacizumab, and erlotinib). Further pediatric development of PG11047 will require better defining a target population and identifying combinations for which there is a tumor-selective cytotoxic effect. The regression observed for an ependymoma xenograft and the exquisite sensitivity of some Ewing sarcoma cell lines to the antiproliferative effects of PG11047 provide leads for further preclinical investigations.