Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia
Ola A. Elgamal, Sydney Fobare, Sandip Vibhute, Abeera Mehmood, Dennis C. Vroom, Mariah L. Johnson, Blaise Stearns, James R. Lerma, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Alice S. Mims, Emily Curran, Ramasamy Santhanam, Susheela Tridandapani, Mitch A. Phelps, Zhiliang Xie, Christopher C. Coss, Sharyn D. Baker, Jeffrey Patrick, Janel K. Ezzell, Jayesh Rai, Jianmin Pan, Shesh N. Rai, Cody Stillwell, Mark Wunderlich, Mouad Abdulrahim, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd
Ola A. Elgamal, Sydney Fobare, Sandip Vibhute, Abeera Mehmood, Dennis C. Vroom, Mariah L. Johnson, Blaise Stearns, James R. Lerma, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Alice S. Mims, Emily Curran, Ramasamy Santhanam, Susheela Tridandapani, Mitch A. Phelps, Zhiliang Xie, Christopher C. Coss, Sharyn D. Baker, Jeffrey Patrick, Janel K. Ezzell, Jayesh Rai, Jianmin Pan, Shesh N. Rai, Cody Stillwell, Mark Wunderlich, Mouad Abdulrahim, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd
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Research Article Oncology Therapeutics

Pyrimidine depletion enhances targeted and immune therapy combinations in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.

Authors

Ola A. Elgamal, Sydney Fobare, Sandip Vibhute, Abeera Mehmood, Dennis C. Vroom, Mariah L. Johnson, Blaise Stearns, James R. Lerma, Jean Truxall, Emily Stahl, Bridget Carmichael, Shelley J. Orwick, Alice S. Mims, Emily Curran, Ramasamy Santhanam, Susheela Tridandapani, Mitch A. Phelps, Zhiliang Xie, Christopher C. Coss, Sharyn D. Baker, Jeffrey Patrick, Janel K. Ezzell, Jayesh Rai, Jianmin Pan, Shesh N. Rai, Cody Stillwell, Mark Wunderlich, Mouad Abdulrahim, Thomas E. Goodwin, Gerard Hilinski, Chad E. Bennett, Erin Hertlein, John C. Byrd

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Figure 5

HOSU-53 significantly enhances the outcome of select FDA-approved AML therapies.

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HOSU-53 significantly enhances the outcome of select FDA-approved AML th...
(A) Using the FLT3-mutant MOLM-13 CDX tumor–bearing model, 10 days after i.v. engraftment, NCG mice (n = 10/group) were enrolled to receive daily p.o. 4 mg/kg or 10 mg/kg HOSU-53 to compare their efficacy with daily p.o. 30 mg/kg gilteritinib (gilt) FLT3 inhibitor or the combination of 4 mg/kg HOSU-53 with gilt. In the gilt combination cohort, 4 mice were euthanized for tissue harvest to determine disease burden, and the remaining 6 mice were kept on study for survival analysis. Black arrow indicates treatment was stopped at day 79. Adjusted FDR P value ***≤0.0001. Vehicle and HOSU-53 arms in this study are shared with Figure 8, A and B. (B) Using the P53-null HL-60 CDX tumor–bearing model, 14 days after i.v. engraftment, NCG mice (n = 10/group) were enrolled to receive 0.4 mg/kg decitabine (Dec) hypomethylating agent (HMA) i.p. as 4 days on/10 days off cycles or daily p.o. 10 mg/kg HOSU-53 or combination of both agents. Dotted black line indicates treatment was stopped and end of study at day 82. P value *≤0.05, ***≤0.0001. (C) Using the FLT3-mutant MOLM-13 CDX tumor–bearing model, 4 days after i.v. engraftment, NCG mice (n = 10/group) were enrolled to receive daily p.o. 4 mg/kg HOSU-53 to compare its monotherapy efficacy with 1.5 mg/kg azacitidine (aza) HMA i.p. for 5 days every 16 day cycles monotherapy or in combination with daily p.o. 25 mg/kg venetoclax (aza/ven) or daily p.o. 4 mg/kg HOSU-53 (aza/HOSU-53). Adjusted FDR P value ***≤0.0001. Supplemental Figure 4 shows all 9 groups done in this study; herein we show the most significant regimens for clarity.