Patient-derived xenograft (PDX) tumors increase growth rate with time

Pearson, Alexander T.; Finkel, Kelsey A.; Warner, Kristy A.; Nör, Felipe; Tice, David A.; Martins, Manoela Domingues; Jackson, Trachette L.; Nör, Jacques E.

doi:10.18632/oncotarget.6919

Cited by 66 publications

(74 citation statements)

References 36 publications

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“…Notably, in the PDX-SCC-M0 model, tumors were ablated completely and did not resume tumor growth for the duration of the study, almost 150 days after a single dose of MEDI0641. Of note, our PDX models exhibited highly variable individual tumor growth rates over time, which is consistent with our previous findings (30). Within a study group, some tumors were considerably larger than others, so if a mouse with a large tumor needed to be euthanized due to protocol requirements, the mean tumor volume for the corresponding group would reflect the loss of that tumor with a sharp decrease in the mean tumor volume calculation.…”

Section: Discussionsupporting

confidence: 92%

“…The PDX models used here represent clinical features observed in patients with HNSCC (29,30). Briefly, the PDX-SCC-M0 model was generated from the local recurrence of a patient that was treated with surgery without radiation or chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

“…Patient-derived xenograft (PDX) tumor models of HNSCC were generated in severe combined immunodeficient (SCID) mice and characterized (29,30). Tumors (PDX-SCC-M0, PDX-SCC-M1, PDX-SCC-M11) were allowed to grow to 200–1000 mm 3 and then were treated with either a single dose of 1 mg/kg MEDI0641, a weekly dose of 0.5 mg/kg MEDI0641 for 2 weeks, a weekly dose of 0.33 mg/kg MEDI0641 for 3 weeks, or non-specific IgG1-PBD control.…”

Section: Methodsmentioning

confidence: 99%

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5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma

Kerk

Finkel

Pearson

et al. 2017

Clinical Cancer Research

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Purpose Loco-regional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, i.e. cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency. Experimental Design Here, we evaluated the efficacy of MEDI0641, a novel antibody-drug conjugate targeted to 5T4 and carrying a DNA-damaging “payload” (pyrrolobenzodiazepine) in preclinical models of HNSCC. Results Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4high tumors displayed lower overall survival than those with 5T4low tumors (p=0.038). 5T4 is more highly expressed in head and neck CSC (ALDHhighCD44high) than in control cells (non-CSC). Treatment with MEDI0641 caused a significant reduction in the CSC fraction in HNSCC cells (UM-SCC-11B, UM-SCC-22B) in vitro. Notably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in 3 patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by 5-fold in the PDX-SCC-M1, and 2-fold in the PDX-SCC-M11 model. Importantly, mice (n=12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for over 200 days, while the control group had 7 recurrences (in 12 mice) (p=0.0047). Conclusions Collectively, these findings demonstrate that an anti-5T4 antibody-drug conjugate reduces the fraction of cancer stem cells and prevents local recurrence, and suggest a novel therapeutic approach for patients with HNSCC.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma

Kerk

Finkel

Pearson

et al. 2017

Clinical Cancer Research

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“…Patient-derived xenograft (PDX) models have been increasingly used in translational cancer research (24). Tumor fragments from a PDX model of ACC (UM-PDX-HACC-5) (21,23) at in vivo passages 5–6 were transplanted into the subcutaneous space of the dorsum of SCID mice (CB.17.SCID; Charles River, Wilmington, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas

Nör

Warner

Zhang

et al. 2017

Clinical Cancer Research

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Purpose Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the anti-tumor effect of a novel small molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with Cisplatin in patient-derived xenograft (PDX) ACC tumors. Experimental design Therapeutic strategies with MI-773 and/or Cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro. The effect of therapy on the fraction of cancer stem cells was determined by flow cytometry for ALDH activity and CD44 expression. Results Combined therapy with MI-773 with Cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL and active Caspase-9 upon MI-773 treatment. Both, single-agent MI-773, and MI-773 combined with Cisplatin, decreased the fraction of cancer stem cells in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a post-surgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (p=0.0097). Conclusions Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the cancer stem cell fraction, sensitized ACC xenograft tumors to Cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction.

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“…In the presence of animal stroma (as in the case of PDX models) or absence of stroma (as in the case of organoid cultures) during tumor propagation, changes to the tumor phenotype may occur. For example, Pearson et al recently showed that PDX tumors of primary human head and neck squamous cell carcinoma and salivary gland adenoid cystic carcinoma increase in growth rate with in vivo passaging [204]. Significant correlations between passage number and histopathological features of higher tumor grade were also observed.…”

Section: New Opportunities and Challenges In 3d Tumor Modelingmentioning

confidence: 99%

Heralding a new paradigm in 3D tumor modeling

et al. 2016

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Numerous studies to date have contributed to a paradigm shift in modeling cancer, moving from the traditional two-dimensional culture system to three-dimensional (3D) culture systems for cancer cell culture. This led to the inception of tumor engineering, which has undergone rapid advances over the years. In line with the recognition that tumors are not merely masses of proliferating cancer cells but rather, highly complex tissues consisting of a dynamic extracellular matrix together with stromal, immune and endothelial cells, significant efforts have been made to better recapitulate the tumor microenvironment in 3D. These approaches include the development of engineered matrices and co-cultures to replicate the complexity of tumor-stroma interactions in vitro. However, the tumor engineering and cancer biology fields have traditionally relied heavily on the use of cancer cell lines as a cell source in tumor modeling. While cancer cell lines have contributed to a wealth of knowledge in cancer biology, the use of this cell source is increasingly perceived as a major contributing factor to the dismal failure rate of oncology drugs in drug development. Backing this notion is the increasing evidence that tumors possess intrinsic heterogeneity, which predominantly homogeneous cancer cell lines poorly reflect. Tumor heterogeneity contributes to therapeutic resistance in patients. To overcome this limitation, cancer cell lines are beginning to be replaced by primary tumor cell sources, in the form of patient-derived xenografts and organoids cultures. Moving forward, we propose that further advances in tumor engineering would require that tumor heterogeneity (tumor variants) be taken into consideration together with tumor complexity (tumor-stroma interactions). In this review, we provide a comprehensive overview of what has been achieved in recapitulating tumor complexity, and discuss the importance of incorporating tumor heterogeneity into 3D in vitro tumor models. This work carves out the roadmap for 3D tumor engineering and highlights some of the challenges that need to be addressed as we move forward into the next chapter.

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Patient-derived xenograft (PDX) tumors increase growth rate with time

Cited by 66 publications

References 36 publications

5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma

5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma

Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas

Heralding a new paradigm in 3D tumor modeling

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