Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity.
Sophia GayleRobert AielloNalin LeelatianJason M BecktaJane BechtoldPatricia BourassaJohanna CsengeryRobert J MaguireDan MarshallRanjini K SundaramJinny Van DoornKelli JonesHunter MooreLori Lopresti-MorrowTimothy ParadisLaurie TylaskaQing ZhangHannah ViscaYana K ReshetnyakOleg A AndreevDonald M EngelmanPeter M GlazerRanjit S BindraVishwas M ParalkarPublished in: NAR cancer (2021)
Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner.
Keyphrases
- cancer therapy
- dna repair
- drug delivery
- dna damage
- endothelial cells
- palliative care
- signaling pathway
- induced pluripotent stem cells
- dendritic cells
- dna damage response
- pluripotent stem cells
- squamous cell carcinoma
- immune response
- adverse drug
- drug induced
- bone marrow
- mesenchymal stem cells
- deep learning
- electronic health record
- lymph node metastasis
- dna binding
- papillary thyroid