In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas.

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Pten signaling in gliomas.

Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the nelfinavir acts along the Akt pathway to radiosensitize cells. However, nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm(3) in the radiation + nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and nelfinavir. (P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas.

https://cancerres.aacrjournals.org/content/canres/67/9/4467.full.pdf

Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir.

Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines

Evidence-based Review on the Use of Proton Therapy in Lymphoma From the Particle Therapy Cooperative Group (PTCOG) Lymphoma Subcommittee Yolanda D. Tseng, MD,* David J. Cutter, MD, DPhil, FRCR,y John P. Plastaras, MD, PhD,z Rahul R. Parikh, MD,x Oren Cahlon, MD,k Michael D. Chuong, MD,{ Katerina Dedeckova, MD, Mohammad K. Khan, MD, PhD,** Shinn-Yn Lin, MD,yy Lisa A. McGee, MD,zz Eric Yi-Liang Shen, MD,yy Stephanie A. Terezakis, MD,xx ShahedN. Badiyan,MD,kk YouliaM. Kirova,MD,{{ Richard T. Hoppe,MD, Nancy P. Mendenhall, MD,***,yyy Mark Pankuch, PhD,zzz Stella Flampouri, PhD,***,yyy Umberto Ricardi, MD,xxx and Bradford S. Hoppe, MD, MPH***,yyy

Evidence-based Review on the Use of Proton Therapy in Lymphoma From the Particle Therapy Cooperative Group (PTCOG) Lymphoma Subcommittee.

BACKGROUND: Nowadays, ionizing radiation is used for several applications in medicine, industry, agriculture, and nuclear power generation. Besides the beneficial roles of ionizing radiation, there are some concerns about accidental exposure to radioactive sources. The threat posed by its use in terrorism is of global concern. Furthermore, there are several side effects to normal organs for patients who had undergone radiation treatment for cancer. Hence, the modulation of radiation response in normal tissues was one of the most important aims of radiobiology. Although, so far, several agents have been investigated for protection and mitigation of radiation injury. Agents such as amifostine may lead to severe toxicity, while others may interfere with radiation therapy outcomes as a result of tumor protection. Metformin is a natural agent that is well known as an antidiabetic drug. It has shown some antioxidant effects and enhances DNA repair capacity, thereby ameliorating cell death following exposure to radiation. Moreover, through targeting endogenous ROS production within cells, it can mitigate radiation injury. This could potentially make it an effective radiation countermeasure. In contrast to other radioprotectors, metformin has shown modulatory effects through induction of several genes such as AMPK, which suppresses reduction/ oxidation (redox) reactions, protects cells from accumulation of unrepaired DNA, and attenuates initiation of inflammation as well as fibrotic pathways. Interestingly, these properties of metformin can sensitize cancer cells to radiotherapy. CONCLUSION: In this article, we aimed to review the interesting properties of metformin such as radioprotection, radiomitigation and radiosensitization, which could make it an interesting adjuvant for clinical radiotherapy, as well as an interesting candidate for mitigation of radiation injury after a radiation disaster. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

Metformin as a Radiation Modifier; Implications to Normal Tissue Protection and Tumor Sensitization.

Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma.

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received R...

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2020.1863631

A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes

A. Maity

Papers

Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma.

A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes

Induction Radiation Prior to Commercial Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Non-Hodgkin Lymphoma

Oral Scientific SessionsRates of Toxicity and Outcomes After Mediastinal Proton Therapy For Relapsed/Refractory Lymphoma

First Clinical Report of Pencil Beam Scanned Proton Therapy for Mediastinal Lymphoma