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Optimizing and predicting the in vivo activity of AT9283 as a monotherapy and in combination with paclitaxel

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Abstract

Objectives

This study aims in optimizing and predicting the in-vivo activity of AT9283 as a monotherapy and evaluating its combination with paclitaxel.

Design and Methods

The effectiveness of AT9283 was examined in several mouse models engrafted with BCR-ABL+ leukemic, human multiple myeloma (MM), and human colorectal carcinoma (HCT116) cells. Dose modeling was performed by analyzing previously published data of AT9283 cancer growth inhibition in vivo. The effects of 2 cycles (7.5–12.5 mg/kg AT9283 twice daily, 5 days/week), 4 cycles (45 mg/kg AT9283 once daily, twice/week), and 3 cycles (10 mg/kg AT9283 twice daily for 5 days or 12.5 mg/kg paclitaxel once/week followed by 5 mg/kg AT9283 twice daily for 4 days) on xenograft growth were quantified to identify the energy yield associated with the different doses.

Results

The continuous infusion regimens (5 days/week) used in the mice engrafted with BCR-ABL+ cells were more efficient than the regimens with twice weekly drug administration used in the mice engrafted with MM cells. The energy yield of the treatment regimen used in the BCR-ABL+ model was perfectly correlated (r = 1) with the AT9283 dose logarithm. An efficient dose-energy model with a perfect fit (R 2 = 1) estimating the energy yield achieved by the different AT9283 doses in optimal regimens was established with the aim of being able to administer patient-specific AT9283 doses. In the HCT116 model, the predicted response to AT9283 monotherapy was nearly identical to the actual response. The regimen combining paclitaxel (1050 mg/L) with low-dose AT9283 (3360 mg/L) used in the HCT116 model was equivalent to an optimal regimen of a higher dose of AT9283 (11,332 mg/L) alone.

Conclusions

Administering AT9283 via continuous infusion optimizes treatment, while combining it with paclitaxel significantly reduces the required AT9283 dose for the advanced-stage tumors with low mitotic index.

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Conflict of Interest

The author declares no conflict of interest.

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Authors and Affiliations

  1. Department of Engineering, Ain Shams University, 217 Alhegaz Street, Alnozha, 11351, Cairo, Egypt

    Emad Y. Moawad

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  1. Emad Y. Moawad
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Correspondence to Emad Y. Moawad.

Additional information

Clinical Practice Points

• AT9283 has been investigated as a monotherapy in patients with advanced solid tumors at centers in the UK, USA, and Canada.

• Although the ability of AT9283 to inhibit growth of cancer and metastasis has been confirmed, previous studies have reported puzzling results about the efficiency of AT9283 therapy due to its cell cycle-specific effect.

• Other studies have suggested paclitaxel to synergize apoptosis in AT9283 therapy.

• Also the antitumor target of AT9283 has not yet been identified to optimize therapy by predicting the response of patients before therapy to provide a protection against treatment failure.

• In the present study, we identify for the first time a predictable antitumor target of AT9283 and evaluate its combination with paclitaxel.

Highlights

<In vivo effects of AT9283 (AT) doses were monitored to identify energy of those doses>

<The energy yield by AT dose was perfectly correlated (r = 1) with the AT dose logarithm>

<Dose-energy model with perfect fit (R2 = 1) was established to estimate the personalized dose>

<Scheduling AT alone in continuous infusion along the doubling time optimizes therapy>

<Combining paclitaxel with AT significantly reduces the required high dose of AT alone>

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Moawad, E.Y. Optimizing and predicting the in vivo activity of AT9283 as a monotherapy and in combination with paclitaxel. J Gastrointest Canc 46, 380–389 (2015). https://doi.org/10.1007/s12029-015-9761-9

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  • DOI: https://doi.org/10.1007/s12029-015-9761-9

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