In patients with cancer, repeated rounds of chemotherapy exhaust the self-renewal capacity of hematopoietic stem cells, leading to prolonged bone marrow suppression, cytopenia and neutropenia. Now, researchers at the Mater Medical Research Institute, The University of Queensland and GlycoMimetics Inc. have mouse data showing that an antagonist of E selectin can alleviate this side effect of chemotherapy.¹

Based on the findings, the team will continue to work together to develop E selectin antagonists, but Mater Research and the biotech are driving different agendas on how to use those antagonists in oncology.

E selectin (SELE; CD62E) belongs to a family of proteins involved in leukocyte homing. Within that family, SELE and SELP (CD62P) are expressed constitutively on the bone marrow endothelium, as well as on endothelial cells from other tissues during injury or inflammation. Both proteins are involved in the homing and engraftment of circulating hematopoietic stem cells (HSCs) and hematopoietic progenitor cells to the bone marrow.

Previous studies showed that quiescent HSCs were enriched near osteoblasts lining the endosteal bone surface and in poorly perfused areas of the bone marrow, leading to the hypothesis that osteoblast factors maintain HSC dormancy and self-renewal.

Because SELE also is expressed within the vascular HSC niche adjacent to bone marrow, the researchers set out to determine whether the protein might also play a role in HSC turnover.

To test that hypothesis, the researchers first worked with Sele knockout mice. HSC turnover in those animals was lower than that in wild-type mice, with increased quiescence of HSCs and a greater potential for self-renewal.

Additional studies showed that HSC quiescence was mediated by the bone marrow microenvironment.

Because Sele deficiency induced quiescence and self-renewal of HSCs, the researchers next investigated whether the HSCs of Sele-deficient mice were more resistant to chemotherapy than HSCs of wild-type mice. Indeed, Sele-deficient mice receiving cyclophosphamide or 5-fluorouracil (5-FU) had greater numbers of HSCs that survived than similarly treated wild-type mice.

The increased survival of the HSCs translated into a survival advantage for the Sele-deficient mice. For example, Sele-deficient mice receiving 5-FU every 10 days had median survival of at least 140 days versus 58 days for wild-type mice receiving 5-FU.

Finally, the team treated mice with GMI-1070, a small, synthetic ­glycomimetic that selectively blocks binding of selectins to their receptors. GlycoMimetics and partner Pfizer Inc. have the molecule in Phase II testing to treat sickle cell disease.

In wild-type mice undergoing serial bone marrow transplantations to rapidly age HSCs, GMI-1070 increased the self-renewal capacity of HSCs compared with saline. Pretreatment with GMI-1070 followed by 5-FU increased HSC survival and self-renewal compared with pretreatment using 5-FU alone and accelerated blood leukocyte recovery.

Results were published in Nature Medicine.

A different Nature Medicine study published one month later also revealed repurposing opportunities using an antidiabetic drug (see Box 1, "More repurpose").

Selectin what's next

"Our work identifies one of the master switches regulating the choice a hematopoietic stem cell makes between quiescence and proliferation. We show that by manipulating the microenvironment around a stem cell, we can alter that cell's response to therapy, its proliferation and self-renewal," said Ingrid Winkler, team leader at Mater Medical Research Institute.

She said Mater Research is working with UniQuest Pty. Ltd., the University of Queensland's commercialization arm, and looking toward clinical trials of E selectin inhibitors to treat the side effects of chemotherapy- and radiotherapy-induced disorders, such as neutropenia.

Meanwhile, GlycoMimetics plans to use its small molecule E selectin antagonists to increase the efficacy of chemotherapeutics in blood cancers.

"E selectin is also known to bind and sequester cancer cells-­particularly blood cancers-within bone marrow. This is a problem because once dosing with chemotherapy ends, leukemic cells can emerge from the bone marrow and result in a relapse," said John Magnani, VP and CSO of GlycoMimetics. "But we and our collaborators at the Dana-Farber Cancer Institute and Harvard Medical School showed that GMI-1070 plus Velcade prevents cancer cells from sequestering within protective niches in the bone marrow, thereby increasing the efficacy of the chemotherapy treatment in a mouse model of multiple myeloma."

Velcade bortezomib is marketed by Takeda Pharmaceutical Co. Ltd. and partner Johnson & Johnson to treat mantle cell lymphoma and multiple myeloma.

The company said it is testing E selectin-specific antagonists in combination with chemotherapy in mouse models of multiple myeloma (MM), acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL).

"Our ultimate goal is to treat certain blood cancers with an orally bioavailable, potent E selectin-specific antagonist in combination with standard-of-care chemotherapy," Magnani said. "We have now rationally designed more potent glycomimetic antagonists that specifically inhibit only E selectin and are optimizing them for oral bioavailability."

GMI-1070 inhibits E selectin but has activity on other members of the family.

GlycoMimetics holds patents covering GMI-1070 and related pan-selectin antagonists and other families of E selectin-specific antagonists.

Mater Research holds patents addressing the use of E selectin antagonists to alleviate the side effects, such as neutropenia, that result from radiotherapy or high-dose chemotherapy. The technology is available for licensing through UniQuest.

Baas, T. SciBX 5(46); doi:10.1038/scibx.2012.1197
Published online Nov. 29, 2012

 REFERENCES

1.   Winkler, I.G. et al. Nat. Med.; published online Oct. 21, 2012; doi:10.1038/nm.2969
Contact: Jean-Pierre Lévesque, Mater Medical Research Institute, South Brisbane, Queensland, Australia
e-mail: jplevesque@mmri.mater.org.au
Contact: Ingrid G. Winkler, same affiliation as above
e-mail: iwinkler@mmri.mater.org.au

2.   Broxmeyer, H.E. et al. Nat. Med.; published online Nov. 18, 2012; doi:10.1038/nm.2991
Contact: Hal E. Broxmeyer, Indiana University School of Medicine, Indianapolis, Ind.
e-mail: hbroxmey@iupui.edu

 COMPANIES AND INSTITUTIONS MENTIONED

Dana-Farber Cancer Institute, Boston, Mass.

GlycoMimetics Inc., Gaithersburg, Md.

Harvard Medical School, Boston, Mass.

Indiana University School of Medicine, Indianapolis, Ind.

Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.

Mater Medical Research Institute, South Brisbane, Queensland, Australia

Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.

Ono Pharmaceutical Co. Ltd. (Tokyo:4528; Osaka:4528), Osaka, Japan

Pfizer Inc. (NYSE:PFE), New York, N.Y.

Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, Japan

UniQuest Pty. Ltd., Brisbane, Queensland, Australia

The University of Queensland, Brisbane, Queensland, Australia