Delineation of a Cellular Hierarchy in Lung Cancer Reveals an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Damelin, Marc; Geles, Kenneth G.; Follettie, Maximillian T.; Yuan, Ping; Baxter, Michelle; Golas, Jonathan; DiJoseph, John F.; Karnoub, Maha; Huang, Shuguang; Diesl, Veronica; Behrens, Carmen; Choe, Sung; Rios, Carol; Gruzas, Janet; Sridharan, Latha; Dougher, Maureen; Kunz, Arthur; Hamann, Philip R.; Evans, Deborah Y.; Armellino, Douglas; Khandke, Kiran; Marquette, Kimberly; Tchistiakova, Lioudmila; Boghaert, Erwin R.; Abraham, Robert T.; Wistuba, Ignacio I.; Zhou, Bin

doi:10.1158/0008-5472.can-10-3919

Cited by 72 publications

(84 citation statements)

References 40 publications

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“…A1mcMMAF exhibited antitumor activity in models that represent a wide range of 5T4 expression levels at doses that did not cause significant adverse effects in cynomolgus monkey. In contrast, the anti-5T4 calicheamicin ADCs that we previously investigated (8,11) were not sufficiently tolerated at efficacious doses, even though calicheamicin has proven suitable for other ADC targets, such as CD22 (25).…”

Section: Discussionmentioning

confidence: 76%

“…The 37622A1 NSCLC patient-derived xenograft (PDX), and the establishment and characterization of primary serum-free culture TUM622 from 37622A1, were described (8).…”

Section: Cancer Cell Lines and Pdxmentioning

confidence: 99%

“…Our previous work has shown that an anti-5T4 ADC bearing the DNA-damaging agent calicheamicin had potent antitumor activity (8,11), but subsequent toxicology studies indicated that it was not well tolerated at exposures required for antitumor activity (unpublished data). Therefore we explored new antibody-linker-payload combinations to target TICs via the 5T4 antigen.…”

Section: Introductionmentioning

confidence: 99%

“…We recently have shown that the 5T4 oncofetal antigen is expressed on proliferating TICs in NSCLC and is associated with the undifferentiated state and the epithelialmesenchymal transition (EMT), which has been linked to TICs and an invasive phenotype (8)(9)(10). 5T4, also known as trophoblast glycoprotein (TPBG), is a cell surface antigen that internalizes rapidly and thus has the potential to efficiently deliver ADCs into tumor cells (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…Expression of 5T4 is associated with advanced disease and/or worse clinical outcome in NSCLC and gastric, colorectal, and ovarian carcinomas (8,(15)(16)(17). 5T4 was shown to modulate CXCR4 function (18) and Wnt signaling (19), yet its specific function remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Sapra

Damelin

DiJoseph

et al. 2013

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumorinitiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non-small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/ cycle Â 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF. Mol Cancer Ther; 12(1); 38-47. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 76%

“…The 37622A1 NSCLC patient-derived xenograft (PDX), and the establishment and characterization of primary serum-free culture TUM622 from 37622A1, were described (8).…”

Section: Cancer Cell Lines and Pdxmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Sapra

Damelin

DiJoseph

et al. 2013

Molecular Cancer Therapeutics

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Selecting Optimal Antibody–Drug Conjugate Targets Using Indication‐Dependent or Indication‐Independent Approaches

Harper¹,

Hollingsworth²

2016

Antibody‐Drug Conjugates

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AMPK promotes the survival of colorectal cancer stem cells

Guo

Han

Tkach

et al. 2018

Anim Models and Exp Med

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Background Colorectal cancer ( CRC ) is the third most commonly diagnosed cancer in males and the second in females worldwide in 2012. In the past 20 years, strong evidence suggests that cancer stem cells are the main culprit of cancer metastasis, chemotherapy resistance, and relapse. Methods To further understand the unique biological properties of cancer stem cells and uncover novel molecular targets to eradicate them, we first established a panel of patient‐derived xenograft ( PDX ) tumor models using tumors surgically removed from human colorectal cancer patients. We then isolated CRC cancer stem cells based on their ALDH activity using fluorescent‐activated cell sorting ( FACS ) and characterized their metabolic properties. Results Interestingly, we found that the CRC cancer stem cells (ie, CRC cells with higher ALDH activity, or ALDH +) express higher level of antioxidant genes and have lower level of reactive oxygen species ( ROS ) than non‐ CRC cancer stem cells (ie, CRC cells with lower ALDH activity, or ALDH−). The CRC cancer stem cells also possess more mitochondria mass and show higher mitochondrial activity. More intriguingly, we observed higher AMP ‐activated protein kinase ( AMPK ) activities in these CRC cancer stem cells. Inhibition of the AMPK activity using 2 AMPK inhibitors, Compound C and Iodotubercidin, preferentially induces cell death in CRC cancer stem cells. Conclusion We propose that AMPK inhibitors may help to eradicate the CRC cancer stem cells and prevent the relapse of CRC s.

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Delineation of a Cellular Hierarchy in Lung Cancer Reveals an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Cited by 72 publications

References 40 publications

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Long-term Tumor Regression Induced by an Antibody–Drug Conjugate That Targets 5T4, an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Selecting Optimal Antibody–Drug Conjugate Targets Using Indication‐Dependent or Indication‐Independent Approaches

AMPK promotes the survival of colorectal cancer stem cells

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