Tahsin M. Khan's research while affiliated with National Institutes of Health and other places

Patients with VHL disease develop tumors affecting various organ systems and anatomical locations starting at an early age. Effective management of this disease involves detecting and intervening on these tumors at appropriate timepoints before the development of symptoms or progression to metastatic disease. Screening and surveillance guidelines based on our understanding of the natural history of VHL disease have been developed to guide management of these complex tumors. The goal is to reduce tumor-related morbidity and mortality while preserving organ functions. This chapter summarizes the screening and surveillance guidelines put forth by various international societies as well as the general management strategies for various VHL lesions. In short, patients with VHL should enter screening and surveillance programs—ideally at institutions with multidisciplinary clinics specializing in VHL disease management—at early age and should undergo annual or biennial follow-up to track their disease progression and determine the appropriate time for intervention if needed.

Cholangiocarcinoma (CCA) is a deadly malignancy with an evolving therapeutic landscape. Although nucleic acid-based evaluations have unveiled some druggable targets, limited options are available for the majority of patients with this disease. We therefore evaluated biliary exosomes by mass spectrometry from 16 patients with CCA, which revealed a 17-fold enhancement of the nuclear export protein XPO7 in CCA-derived biliary exosomes. IHC analysis of XPO7 expression in CCA tumors from 170 patients unexpectedly demonstrated intense cytoplasmic staining in 30% of the samples, which correlated with abbreviated survival. Within the cytosol, we demonstrate that XPO7 exists in a molecular complex with the serine/threonine kinase SLK. shRNA-mediated knockdown of either XPO7 or SLK abrogated tumor organoid formation in vitro, and reduced orthotopic tumor formation and substantially altered tumor morphology using athymic mice. A kinome screen of FDA-approved drugs revealed tivozanib inhibits SLK (IC50= 81.8 nM), which we confirmed using crystallography. Tivozanib treatment reduced tumor organoid formation in vitro and induced tumor regression in vivo using murine xenografts with resulting morphology similar to XPO7 and SLK knockdown tumors. Importantly, site-directed mutagenesis of SLK was used to confirm the observed phenotypic alterations secondary to SLK inhibition. Signal transduction studies with SLK knockdown in CCA cell lines demonstrated downregulation of PI3K-AKT-mTOR signaling with further effects on DNA damage resulting in G2 cell cycle arrest. Moreover, tivozanib demonstrated anti-tumor activity and increased apoptosis in established CCA patient-derived xenografts with cytoplasmic XPO7 expression. Using ex vivo tumor slice cultures, tivozanib significantly increased tumor cell apoptosis in XPO7/SLK-expressing tumors (N=3) but not in tumors without this expression pattern (N=6). Further evaluation of these tivozanib-treated tumor slice cultures demonstrated a reduction in the expression of phosphorylated mTOR (S2448), AKT (T308), S6 (S235/236) in the high XPO7/SLK-expressing tumors but not in tumors without this expression pattern. Lastly, tivozanib monotherapy demonstrated in vivo efficacy with arrest of tumor progression (RECIST stable disease) in an ongoing clinical trial (NCT04645160). Citation Format: Priyanka P. Desai, Tahsin M. Khan, Reed I. Ayabe, Emily Smith, Surajit Sinha, Ashley Rainey, Yuri Lin, Tracey Pu, Kenneth Lubrice, Leila Sarvestani, Sarfaraz Akmal, Shahyan Rehman, Kirsten Remmert, Michael Yaffe, Craig Thomas, John Brognard, Jonathan M. Hernandez. A cytosolic complex between exportin-7(XPO7) and ste20-like kinase (SLK) regulates PI3K-AKT-mTOR signaling in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB172.

Introduction: Metastatic outgrowth and colonization requires that disseminated tumor cells simultaneously compensate for alterations in nutrient availability, counteract oxidative stress, and evade host innate and adaptive immune surveillance. The mechanistic underpinnings of how these vital processes are coordinated is not understood. Experimental procedures: Using intrasplenic injection (liver metastases) and tail vein injection (lung metastases), we employed a gain-of-function cDNA screen in mice to identify regulators of colonization. In doing so, we identified GCN1 signaling as indispensable to the disseminated pancreatic cancer cell. Summary of unpublished data: Specifically, we demonstrate that alterations in nutrient availability encountered in target organs (liver, lung) trigger pancreatic cancer cells to utilize GCN1 stress signaling to upregulate the expression of serine, folate, and methionine pathway biosynthetic enzymes together with amino acid transporters through the integrated stress response effector ATF4. These pathways act in concert to facilitate acquisition of metabolites critical for cellular functions including maintenance of redox homeostasis. Surprisingly, we found that GCN1 also functions in the nucleus, where it interacts with HNRNPK to destabilize the transcripts encoding natural killer (NK) cell activation ligands and key regulators of major histocompatibility complex (MHC) class I molecules. Intriguingly, we identified an endogenous protein rheostat, IMPACT, for GCN1’s dual functions and show that IMPACT expression is lost in human pancreatic metastases through DNA methylation. IMPACT overexpression in pancreatic cancer cell lines inhibited the integrated stress response effector ATF4 to retard nutrient uptake and activated the expression of NK cell ligands and MHC class I molecules to fuel anti-tumor immune responses. Conversely, IMPACT knockout enabled successful acquisition of metabolic intermediaries in response to nutrient alterations and suppressed anti-tumor immune response to accelerate metastatic outgrowth. Accordingly, bioinformatic analyses of human pancreatic cancer showed that while the expression of GCN1 increases in metastatic disease, the expression of IMPACT is lost, correlating with significantly shorter survival of GCN1-high, IMPACT-low expressing tumors. Finally, IMPACT overexpression synergized with immune checkpoint inhibitors in mice to eliminate macrometastases formation. Conclusion: In summary, we have identified IMPACT as an immunometabolic checkpoint that restrains GCN1-mediated metabolic plasticity and GCN1-mediated suppression of innate and adaptive immune surveillance. We propose that drugs that can restore IMPACT expression or IMPACT mimetic agents will have therapeutic value for patients with pancreatic cancer. Citation Format: Surajit Sinha, Abir Panda, Zeribe Nwosu, Rodrigo Neves Das, Xu Ke, Elke van Beek, Alexander J. Rossi, Reed I. Ayabe, James McDonald, Michael M. Wach, Samantha Ruff, Priyanka P. Desai, David Sun, Martha E. Teke, Emily A. Verbus, Areeba Saif, Shreya Gupta, Tahsin Khan, Leila Sarvestani, Carrie E. Ryan, Jacob Lambdin, Kirsten Remmert, Emily Smith, Kenneth Luberice, Stephie Lux, Imani A. Alexander, Tracey Pu, Allen Luna, Sarfraz R. Akmal, Shahyan Rehman, Ashley Rainey, Hanna Hong, Yuri Lin, Samantha Sevilla, Gasmi Billel, Sivasish Sindiri, Todd Prickett, King Chan, Eileen Li, Xiaolin Wu, Nicholas D. Klemen, Giorgio Trinchieri, Costas A. Lyssiotis, Jeremy Davis, Pankaj K. Singh, Steven A. Rosenberg, Michael B. Yaffe, Filippo Giancotti, Ethan M. Shevach, Jonathan M. Hernandez. IMPACT restrains immuno-metabolic GCN1 signaling to govern pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C106.

Background and objectives: In 2003, the Society of Surgical Oncology (SSO) initiated a breast surgical oncology fellowship, which has now grown to 60 SSO accredited programs as of 2021. Limited knowledge exists on the traits of successful applicants and the factors influencing the rank list. Methods: A web-based, anonymous survey was sent to all SSO Breast Surgical Oncology Fellowship program directors. The survey consisted of 26 questions. Descriptive statistics were used to analyze survey responses and evaluate impact on applicant interview and rank list. Results: Thirty-four programs (57% response rate) completed the survey. Programs received an average of 70 applications and granted 24 interviews. Most programs reported a minimum ABSITE cut-off score (n = 28, 82%) and a defined publication requirement (n = 22, 65%), including a first-author requirement (n = 18, 53%) to extend an invitation to interview. For postinterview rank, applicant interpersonal skills were highly valued. The interview was the most important aspect for the rank list. Conclusions: Many programs have ABSITE and publication thresholds before offering an interview. Upon receiving interview invitation, the applicant's interview performance, interpersonal skills, and letters of recommendation were the most important aspect in rank list decision making.

Introduction We evaluate National Institutes of Health (NIH) data to describe endocrine surgical research performed by surgeons in the United States. Methods An internal NIH database was queried for endocrine surgery-related grants awarded to surgeons in 2010, 2015, and 2020. The grants were then compared based on cost, grant type, research type, and endocrine topic. Results Eighteen grants ($6.4M) focused on endocrine surgery-related research topics were identified in 2020, 17 ($7.3M) in 2015, and 11 ($3.8M) in 2010. In 2020, 14 grants were basic science and 4 were clinical outcomes, and pancreatic endocrine disease and thyroid disease each comprised 6 grants. R01 and R21 grants comprised 10 (55.6%) of the grants in 2020, compared to 10 (58.5%) in 2015 and 8 (72.7%) in 2010, while K08 and K23 grants increased to 4 (22.2%) in 2020 from 2 (11.8%) in 2015 and none in 2010. Conclusion There were more K-awards focused on endocrine surgery-related research in 2020 compared to 2015 and 2010, suggesting the pipeline is growing.

Background Post-operative pancreatic fistula (POPF) is a serious complication following pancreas surgery. We aimed to establish factors associated with POPF specifically in patients with pancreatic neuroendocrine tumors (PNET). Methods The 2014–2018 American College of Surgeons National Surgical Quality Improvement Program database was querried for patients undergoing resection for PNET. The impact of patient, tumor, and operative factors on POPF formation was evaluated. Results 3532 patient underwent resections for PNET. The POPF rate was significantly higher in patients with PNET (24.8%) versus non-PNET (16.4%) (p < 0.0001). Male sex (OR 1.45, 95% CI 1.11–1.89), enucleation (OR 3.14, 95% CI 1.10–8.98), pancreaticoduodenectomy (OR 1.51, 95% CI 1.13–2.03), small duct size <3 mm (OR 3.24, 95% CI 1.62–6.48), and soft gland texture (OR 1.81, 95% CI 1.18–2.77) were independently associated with POPF in PNET patients on multivariable analysis. Conclusions POPF is more common in patients undergoing resection for PNET and is dictated primarily by surgical approach and gland characteristics.

Background and objectives: Guidelines for Stage II colon cancer recommend adjuvant chemotherapy (AC) only for tumors with high-risk features, but long-term outcomes data are mixed. We aimed to determine if AC was associated with a survival benefit in this population. Methods: Patients were identified from the National Cancer Database and included if they met the following criteria: diagnosis of Stage II colon cancer, surgery, survival data, and complete data on six high-risk features. The cohort of 57 335 patients was stratified by receipt of AC. Subgroup analysis was performed on patients under the age of 65 years with no comorbidities. Overall survival (OS) was the primary endpoint. Results: An increasing number of high-risk features was associated with significantly decreased median OS. AC was associated with significantly increased OS for patients with 0, 1, 2, and ≥3 high-risk features. On subgroup analysis, receipt of AC was associated with a reduced risk of death (hazard ratio: 0.66; confidence interval: 0.59-0.74). For patients in the subgroup who had a T4 tumor, AC was associated with increased OS (92.7 vs. 83.6 months). Conclusions: AC should be considered for all younger, healthy patients with Stage II colon cancer and may be associated with a survival benefit for patients with T4 disease.

Wild-type KIT and PDGFRA gastrointestinal stromal tumors (GIST) are rare tumors with limited treatment options. We sought to determine the clinicopathologic features of wild-type GIST and identify factors that influence overall survival (OS) using a large national database. Retrospective evaluation of patients with wild-type GIST in the National Cancer Database (NCDB) was performed. Demographic, clinicopathologic, and treatment data were analyzed. Features associated with OS were investigated using Kaplan–Meier analysis and Cox proportional hazards model. 244 patients with median diagnosis age of 59 years (95% CI 57–63) were identified. The stomach was the most common primary site (57%) followed by the small intestine (35%). Surgical resection was performed on 85% of patients and 53% of patients received systemic therapy. Factors associated with decreased OS on multivariable analysis included small intestine primary (HR 2.72, 95% CI 1.13–6.69, P = 0.026) and > 5 mitoses per 50 HPF (HR 4.77, 95% CI 1.86–13.2, P = 0.001). Wild-type GISTs may be identified in older patients, with most arising in the stomach and small bowel. Surgery remains the principal treatment modality. Small intestine primary site and high mitotic count were associated with abbreviated OS.