No abstract

No abstract

Pituitary adenomas are benign intracranial neoplasms that are frequently well-controlled with standard treatments that include surgical resection, radiotherapy, and agents that modulate hormonal excess. Unfortunately, a subset of patients remains uncontrolled or develops complications from these interventions. For these patients, chemotherapy is an additional treatment option that could improve outcomes. Temozolomide is an oral chemotherapy with a favorable side-effect profile that has shown activity against pituitary adenomas. Its non-overlapping toxicity and ability to induce rapid tumor regression renders it a potentially important adjunctive treatment. In patients with tumors that cannot be optimally addressed with standard treatments, there may be a role for early initiation of temozolomide.

. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338350 doi: bioRxiv preprint first posted online Jun. 4, 2018; 3 Nitrogen-containing bisphosphonates (N-BPs) are the standard treatment for osteoporosis and several other bone diseases 11,12 . Certain N-BPs (pamidronate (Aredia®), zoledronate (Zometa®)) are also routinely prescribed to prevent skeletal complications in patients with multiple myeloma and with bone metastases from other malignancies, including breast and prostate cancer 13 . However, because N-BPs cause rare yet serious side-effects, such as atypical fractures and osteonecrosis of the jaw, many patients avoid taking them [5][6][7]11 , causing the number of prescriptions to plummet over 50% in the last decade 7,14 . Thus, there is a sizeable and growing need to better understand the genetic factors that might underlie the onand off-target clinical effects of the N-BPs.A goal of personalized medicine is to identify biomarkers that underlie drug responsiveness. In the case of the N-BPs, it can be said that there are limited personalization options owing to the limited number of genes implicated in the mechanism of action of N-BPs on bone. was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/338350 doi: bioRxiv preprint first posted online Jun. 4, 2018; 4 understanding of the molecular mechanisms by which N-BPs regulate the major bone cell types would be improved by further studies.To provide insight into the mechanism(s) of N-BPs action, we performed a genetic screen to identify human genes required for the anti-proliferative effects of N-BPs (Fig. 1a) Other genes identified in our alendronate haploid screen (SNTG1, PLCL1, and EPHB1) have been previously connected to N-BP action on bone cells and/or human bone diseases [28][29][30] . To systematically evaluate all "hits" we identified (i.e., the 185 genes with FDR p-value < 0.05, see Fig. 1b), we developed a computational approach utilizing a molecular biology-optimized version of PubMed (currently at ~27M records) to assess to what extent our haploid screen identified genes were cited as relevant to human studies that focus on bone (see "PubMed citation analysis" in the Methods section for details). We asked whether our alendronate haploid screen hits were mentioned in publications co-occurring with the term "bone" vs. other tissues along with identifiers of genome-wide screening, namely the strings, "GWAS" or "genome-wide" (Fig. 1c). Indeed, our alendronate screen hits were enriched in publications co-mentioning "bone" and genome-wide studies compared to control gene sets (Fig. 1d, Supplementary Table 1b). This . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed...

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP–mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.