When Carole Gross was diagnosed with breast cancer, she knew having radiation therapy close to her home was essential. She chose Penn Radiation Oncology, located on the campus of Doylestown Hospital’s campus, for its convenience and its reputation.

It was there she met William Rate, MD, PhD, radiation oncologist.

“Dr. Rate was amazing,” she says. “He asked me about myself – he put me as a person before my cancer diagnosis. He just made me feel I was important – that I was comfortable with the whole process. And, he presented information to me in a very understanding and reassuring way.”

When a scan showed something on Carole’s hip, Dr. Rate personally consulted with his colleagues and asked Carole if he could make appointments for her so she could focus on her treatments.

“Within a half hour of Dr. Rate’s phone call, all of my imaging studies and reports were sent to another specialist I could see for my hip,” says Carole. “Everything was seamless, but Dr. Rate made me so comfortable with the process.”

Carole’s treatments spanned her children’s summer break, and she was able to bring her kids with her to her treatments. She jokes that her kids felt comfortable, because they knew their mom was being treated so well.

“Penn Radiation Oncology allowed me to have the same level of treatment as the Abramson Cancer Center, within my own community,” says Carole. “It was a wonderful opportunity, and I wouldn’t have wanted my cancer treatment anywhere else.”

Dr. Rate, radiation oncologist

About Penn Radiation Oncology at Doylestown Hospital

Penn Medicine Radiation Oncology at Doylestown, located on the campus of Doylestown Hospital, offers a full range of radiation oncology services and on-site access to Penn Neurosurgery, including:

• Intensity Modulated Radiation Therapy (IMRT)
• Image-guided radiation therapy (IGRT)
• Conformal Radiation Therapy (CRT)
• Treatment planning for radiation therapy
• Second opinion and consultation services
• Supportive care and symptom management services

Other Penn Medicine Radiation Oncology Locations:

If our Doylestown location is not convenient for you, please consider these other Penn Radiation Oncology locations:

• Penn Radiation Oncology Chestnut Hill
• Penn Radiation Oncology Chester County Hospital
• Penn Radiation Oncology Kennett Square
  
• Penn Radiation Oncology Pennsylvania Hospital
• Penn Radiation Oncology Perelman Center for Advanced Medicine
• Penn Radiation Oncology Radnor
• Penn Radiation Oncology Valley Forge

Following mutations in BRAF and NRAS, the RAC1 c.85C>T single-nucleotide variant (SNV) encoding P29S amino acid change represents the next most frequently observed protein-coding hotspot mutation in melanoma. However, the biologic and clinical significance of the RAC1 P29S somatic mutation in approximately 4% to 9% of patients remains unclear. Here, we demonstrate that melanoma cell lines possessing the RAC1 hotspot variant are resistant to RAF inhibitors (vemurafenib and dabrafenib). Enforced expression of RAC1 P29S in sensitive BRAF-mutant melanoma cell lines confers resistance manifested by increased viability, decreased apoptosis, and enhanced tumor growth in vivo upon treatment with RAF inhibitors. Conversely, RNAi-mediated silencing of endogenous RAC1 P29S in a melanoma cell line with a co-occurring BRAF V600 mutation increased sensitivity to vemurafenib and dabrafenib. Our results suggest RAC1 P29S status may offer a predictive biomarker for RAF inhibitor resistance in melanoma patients, where it should be evaluated clinically. Cancer Res; 74(17); 1–8. ©2014 AACR.

Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70–Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70–Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70–Bag3 complex may offer an appealing anticancer target. Cancer Res; 74(17); 1–10. ©2014 AACR.

Isocitrate dehydrogenase 1 (IDH1) mutations occur in most lower grade glioma and not only drive gliomagenesis but are also associated with longer patient survival and improved response to temozolomide. To investigate the possible causative relationship between these events, we introduced wild-type (WT) or mutant IDH1 into immortalized, untransformed human astrocytes, then monitored transformation status and temozolomide response. Temozolomide-sensitive parental cells exhibited DNA damage (γ-H2AX foci) and a prolonged G2 cell-cycle arrest beginning three days after temozolomide (100 μmol/L, 3 hours) exposure and persisting for more than four days. The same cells transformed by expression of mutant IDH1 exhibited a comparable degree of DNA damage and cell-cycle arrest, but both events resolved significantly faster in association with increased, rather than decreased, clonogenic survival. The increases in DNA damage processing, cell-cycle progression, and clonogenicity were unique to cells transformed by mutant IDH1, and were not noted in cells transformed by WT IDH1 or an oncogenic form (V12H) of Ras. Similarly, these effects were not noted following introduction of mutant IDH1 into Ras-transformed cells or established glioma cells. They were, however, associated with increased homologous recombination (HR) and could be reversed by the genetic or pharmacologic suppression of the HR DNA repair protein RAD51. These results show that mutant IDH1 drives a unique set of transformative events that indirectly enhance HR and facilitate repair of temozolomide-induced DNA damage and temozolomide resistance. The results also suggest that inhibitors of HR may be a viable means to enhance temozolomide response in IDH1-mutant glioma. Cancer Res; 74(17); 1–9. ©2014 AACR.

Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered phospholipid metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed 31P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation. 31P-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by 31P high-resolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro
31P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-R132H mutation alters phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma. Cancer Res; 74(17); 1–10. ©2014 AACR.