Sachin R. Jhawar

Oncolytic Viruses—Natural and Genetically Engineered Cancer Immunotherapies

There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer.

Diagnostic Medical Imaging in Pediatric Patients and Subsequent Cancer Risk

The use of diagnostic medical imaging is becoming increasingly more commonplace in the pediatric setting. However, many medical imaging modalities expose pediatric patients to ionizing radiation, which has been shown to increase the risk of cancer development in later life. This review article provides a comprehensive overview of the available data regarding the risk of cancer development following exposure to ionizing radiation from diagnostic medical imaging. Attention is paid to modalities such as computed tomography scans and fluoroscopic procedures that can expose children to radiation doses orders of magnitude higher than standard diagnostic x-rays. Ongoing studies that seek to more precisely determine the relationship of diagnostic medical radiation in children and subsequent cancer development are discussed, as well as modern strategies to better quantify this risk. Finally, as cardiovascular imaging and intervention contribute substantially to medical radiation exposure, we discuss strategies to enhance radiation safety in these areas.

Stereotactic Body Radiation Therapy in Non-Surgical Patients with Metastatic Spinal Disease and Epidural Compression: A Retrospective Review

BACKGROUND In the setting of spinal metastases with epidural cord compression, radiosurgery is often only considered when there is sufficient separation between the epidural disease and the spinal cord. However, in patients who are nonsurgical candidates or those who prefer nonoperative management, there may be a benefit from stereotactic body radiation therapy, even when the epidural target is closer than the traditionally referenced 3 mm distance from the spinal cord. The purpose of this retrospective study is to evaluate our institutions experience in treating 20 such patients. METHODS We reviewed records of all patients treated with stereotactic body radiation therapy for spinal metastases at our institution from January 2010 to January 2016, with follow-up through December 2016. The primary end point was local progression of disease. Local progression was defined as clear radiographic disease growth on follow-up imaging or worsening clinical symptoms in the absence of evidence for radiation myelopathy. RESULTS Local control was obtained in 55% of patients meeting these criteria without a single case of radiation myelitis. Most patients with disease progression were able to undergo additional local treatment. CONCLUSIONS Although local control was less than expected when compared with spine radiosurgery with adequate separation between the target and spinal cord, this treatment appears to be a viable option in the nonsurgical candidate.

VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells

Purpose DNA double-strand breaks (DSBs) can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). We demonstrate the selectivity of VX-984, a DNA-PK inhibitor, using assays not previously reported. Experimental Design The class switch recombination assay (CSR) in primary B cells was used to measure efficiency of NHEJ. A cellular reporter assay (U2OS EJ-DR) was used to assess the efficiency of HR and NHEJ in cells treated with VX-984. Immunofluorescence assays (IF) evaluated γ-H2AX foci for DSB repair kinetics in human astrocytes and T98G glioma cells. Western blotting was used to evaluate phosphorylation of DNA-PKcs substrates. Results We found a dose-dependent reduction in CSR efficiency with VX-984, and through the EJ-DR assay, dramatic dose-dependent increases in HR and mNHEJ. Immunofluorescence assays showed an inability of malignant cells to resolve γ-H2AX foci in the presence of VX-984. Radiation-induced phosphorylation of DNA-PK substrates was further reduced by treatment with VX-984. Conclusions VX-984 efficiently inhibits NHEJ, resulting in compensatory increases in alternative repair pathways, increases DSBs, and appears to affect transformed cells preferentially.

Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

Radiation Therapy for Tracheobronchial Metastases from Head and Neck Squamous Cell Carcinoma

Tracheobronchial metastases from head and neck squamous cell carcinoma (HNSCC) represent a rare occurrence, with few reported cases in the literature. Here, we present two patients with HNSCC who developed tracheobronchial metastases at different time points in their disease course. Patient 1 presented with a localized tonsillar primary, underwent tonsillectomy and post-operative radiation therapy to the tumor bed and bilateral neck, and experienced multiple subsequent metastases in different locations throughout the tracheobronchial tree. Each time, she received surgery and/or chemoradiation therapy to the metastatic lesion(s). Patient 2 presented with a supraglottic primary metastatic to the carina and both mainstem bronchi, and, based on patient 1’s recurrence pattern and a suspicion for direct tumor extension, was treated upfront with definitive chemoradiation from the supraglottis down through much of the tracheobronchial tree. A year out from treatment, patient 2 has achieved excellent locoregional control with few treatment-related toxicities but unfortunately has developed new liver metastases not seen on pre-treatment imaging. This case highlights the difficulty in ascertaining the extent of metastatic spread for HNSCC patients with isolated tracheobronchial metastases and describes our approach to delivering curative-intent radiation therapy.

Tweet for the cure: A snapshot of Twitter usage by 3 U.S. oncologic professional societies

Purpose Medical societies are incorporating Twitter to communicate with their members and connect with patients. This study compares the online presence of 3 major oncologic societies. Methods and materials All available tweets in 2014 by the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and Society of Surgical Oncology (SSO) were collected. We analyzed whether posts were original content or retweets. The monthly tweet rate was followed to assess trends. We created 2 new metrics, supporter ratio and tweet density, to correlate online presence and engagement with offline membership breadth. The supporter ratio is the number of people following the organization divided by the number of registered members of each society. The tweet density is the total number of posts divided by the number of registered members of each society. Results In February 2015, ASCO, ASTRO, and SSO had 36,385; 10,899; and 2721 members, respectively. ASCOs Twitter handle had 33,974 followers, with a supporter ratio of 0.93. A total of 2563 original tweets and 1416 retweets were estimated, which represents a tweet density of 0.11. @ASTRO_org had 5445 followers and a supporter ratio of 0.50. In 2014, ASTRO posted 415 original content tweets and 9 retweets, with a tweet density of 0.039. SSO had a supporter ratio of 0.91 on the basis of 2481 followers. In 2014, SSO posted 207 original tweets and 190 retweets, with a tweet density of 0.15. An increase in tweets and retweets was seen during the month of each societys annual meeting. ASTROs 61% increase in September 2014 was smaller than SSOs 462% and ASCOs 84%. Conclusion ASTROs use of Twitter lags behind ASCO and SSO. Although all 3 societies show increased Twitter use during their annual meetings, they should work toward more meaningful engagement throughout the year. The new metrics of tweet density and supporter ratio will serve as benchmarks for member engagement in future studies.