Preclinical Development of Novel Therapies

Identified and destroyed blood vessels providing circulation to tumors by attaching a small peptide to a toxic molecule that specifically targets the cells that form these blood vessels, providing proof-of-concept that peptides can be synthesized and directed to kill particular cancers.

Arap MA, Lahdenranta J, Mintz PJ, Hajitou A, Sarkis AS, Arap W, Pasqualini R. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell. 2004;6(3):275-284.

Established the feasibility of “anti-obesity therapy” based upon targeted induction of apoptosis in the vasculature of adipose tissue.

Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004;10(6):625-632.

Discovered that a synthetic peptide corresponding to the envelope protein of HIV-1 can inhibit entry of the virus into human cells, making this peptide a candidate for therapeutic intervention for patients with HIV/AIDS.

Nehete PN, Vela EM, Hossain MM, Sarkar AK, Yahi N, Fantini J, Sastry KJ. A post-CD4-binding step involving interaction of the V3 region of viral gp120 with host cell surface glycosphingolipids is common to entry and infection by diverse HIV-1 strains. Antiviral Res. 2002;56(3):233-251.

Nehete PN, Arlinghaus RB, Sastry KJ. Inhibition of human immunodeficiency virus type 1 infection and syncytium formation in human cells by V3 loop synthetic peptides from gp120. J Virol. 1993;67(11):6841-6846.

Showed that PTEN activation contributes to tumor inhibition by trastuzumab (Herceptin) and that loss of PTEN predicts resistance to trastuzumab in HER2-positive breast cancer patients, leading to combination therapies to overcome Herceptin resistance.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117-127.

Identified cellular self digestion as a target for cancer therapy; identified potential compounds, such as the phenothiazines, to induce cellular self digestion, providing the first evidence of a mechanism for the role of nutrients and energy metabolism in cell survival.

Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB. The energy sensing LKB1-AMOK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis.  Nat Cell Biol. 2007;9:218-224.

Discovered the abnormal Bcr-Abl protein that causes Philadelphia-positive acute lymphoblastic leukemia. This work formed the foundation for developing drugs, such as imatinab, that suppress the aberrant Bcr-Abl kinase, resulting in remarkable responses with minimal side effects.

Kurzrock R, Shtalrid M, Romero P, Kloetzer SB, Talpaz M, Trujillo JM, Blick M, Gutterman JU. A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukemia. Nature 1987;325:631-635.