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Houghton Lab

Peter Houghton, PhD

Rank: Professor
Department: Molecular Medicine
Office: 2.110.12
Tel: 210.562.9056
houghtonp@uthscsa.edu:

Our studies aim to understand the mechanisms of cancer initiation in children and use this information to develop more effective and less toxic treatments that will increase the cure rate and improve the quality of life for cancer survivors.

UTHSA Faculty Profile: Peter J. Houghton,, PhD

Publications

Grants & Awards

Lab Research

Research Project A

Childhood Glioma

The most common brain tumor in children is astrocytoma. These tumors can occur in any part of the brain and are derived from astrocytes, a type of glial cell that provides nutrition to neurons in the brain. Astrocytoma may occur as familial cancer or as sporadic cancer. There is an increased risk of low-grade astrocytoma with a genetic condition called neurofibromatosis 1 (NF1). These familial astrocytomas are associated with mutations in the NF1 gene that encodes a negative regulator of RAS, leading to constitutive signaling through the MAP kinase and PI3 kinase pathways and continued cell proliferation. Sporadic low-grade astrocytoma, often referred to as Juvenile Pilocytic Astrocytoma (JPA), is also associated with the activation of the MAP kinase signaling pathway. These tumors are indolent (slow-growing) and well-circumscribed without invasion into surrounding brain tissue. Genomic studies have shown that ~90% of these low-grade tumors have a tandem duplication involving the KIAA1549 and BRAF genes that generate constitutively active KIAA1549::BRAF fusions. Higher-grade tumors tend to have activating point mutations of BRAF, most frequently the V600E variant. Such activating mutations are identified in diffuse astrocytomas (23%), gangliogliomas (33%), and pleomorphic xanthoastrocytoma (70%). Some 10-15% of pediatric glioblastomas and many epithelioid glioblastomas also carry this mutation. Drawing from available databases (ACS and CBTRUS), approximately 1400 new pediatric BRAF mutant brain tumors and 350 adult brain tumors are diagnosed annually.

We identified a drug that inhibits a kinase (MEK) downstream in the signaling cascade and causes the arrest of proliferation and death of these cancer cells. Selumetinib has recently completed phase I and II testing through the Pediatric Brain Tumor Consortium (PBTC) and Children’s Oncology Group (COG). Selumetinib shows promising activity. This project builds upon our initial work to develop effective therapies that prevent or retard the emergence of drug-resistant cells and to explore the therapeutic value of combining selumetinib (or other MEK inhibitors) with radiation therapy.

Research Project B

The Pediatric In Vivo Testing Program (PIVOT)

The PPTC builds upon fifteen years of testing novel agents against panels of cell lines in vitro and tumor xenografts models in mice that represent childhood solid tumors, brain tumors, and acute lymphoblastic leukemias. Over 100 drugs, or drug combinations, have been tested in approximately 100 models of childhood cancer (kidney cancers, sarcomas, neuroblastoma, liver cancers, brain cancers, and acute lymphoblastic leukemia.) These studies have identified novel drugs and drug combinations that are now in a clinical trial.

Research Project C

Signaling Pathways in Childhood Sarcoma

Our earlier studies have identified insulin-like growth factor (IGF) signaling as maintaining the proliferation of sarcoma cells and being involved in angiogenesis by regulating vascular endothelial cell response to VEGF. The current studies, supported through a Program Project Grant from NCI, aim to identify resistance mechanisms to therapeutics that target the IGF-axis. These studies integrate IGF, STAT3, and NFκB signaling pathways in childhood sarcoma models both in vitro and in vivo.

Research Project D

The CPRIT Texas Pediatric Testing Program

Through the combined efforts of Drs. Houghton, Kurmasheva, and Zheng at GCCRI, with support from the Cancer Prevention and Research Institute of Texas (CPRIT, Texas Pediatric Patient Derived Xenograft Facility, RP160716), we have generated approximately 160 new models of pediatric cancers. The list of CPRIT-derived solid tumor and leukemia PDX models are shown in Tables 1 and 2.