Faculty Bibliography

Oncogenic KRAS is amongst the key genetic drivers for initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with Kras^G12D specific siRNA (iExoKras^G12D) reveal a biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKras^G12D in the iEXPLORE (iExoKras^G12D in Pancreatic Cancer) Phase I study employed a non-randomized single-arm classical 3 + 3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) (NCT03608631). The primary outcomes included safety, tolerability and target engagement, and the secondary outcomes aimed to assess disease control. Patients with advanced metastatic disease were enrolled after failure of multiple lines of therapy. iExoKras^G12D therapy was well-tolerated: the primary outcomes were met with iExoKras^G12D showing no dose-limiting toxicity. The maximum tolerated dose was not reached even at the highest dose. In some cases, iExoKras^G12D therapy was associated with stable disease response (secondary outcome). Downregulation of KRAS^G12D DNA and suppression of phospho-Erk was documented together with an increase in intratumoral CD8⁺ T cells following treatment. The CD8⁺ T cell recruitment priming by iExoKras^G12D informed on potential efficacy of immune checkpoint therapy and lead to validation testing in preclinical PDAC models. Combination therapy of iExoKras^G12D and anti-CTLA-4 antibodies, but not anti-PD1, revealed robust pre-clinical anti-tumor efficacy via FAS mediated CD8⁺ T cell anti-tumor activity. This first-in-human, precision medicine clinical trial and supporting preclinical functional studies offer new insights into priming of immunotherapy by oncogenic Kras inhibitor for future opportunistic combination therapy for PDAC patients.

Intraductal papillary mucinous neoplasms (IPMNs) are cystic lesions and bona fide precursors of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Although ∼90% of IPMNs are detected before PDAC forms, markers distinguishing benign from malignant disease are lacking, resulting in an abundance of unnecessary, invasive surgeries. Recent studies show that pancreatic precancer assumes a pyloric phenotype. To identify the regulators of this plasticity, cell lines, organoids, tumors from mouse models of IPMNs, and patient samples underwent multiplex immunostaining, RNA sequencing, glycosylation profiling, and computational analysis. These data revealed that GNAS^R201C drives an indolent phenotype in IPMNs by amplifying a differentiated, pyloric phenotype through SPDEF/CREB3L1, which is characterized by distinct glycans. Acting as a glycan rheostat, GNAS^R201C elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3'-sulfo-Le^A/C are mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.

Early detection is key to improving survival and mortality from pancreatic cancer. Traditional periodic screening for cancer in an asymptomatic population is infeasible and not recommended for this low-incidence disease. We describe a novel approach we call "heuriskance" (hyou-ris-kance) wherein a systematic search for and onetime workup of a "heurisk" (hyou-risk) leads to earlier detection of cancer. A heurisk is an early warning sign with three defining characteristics: i) indicates higher-than-threshold-probability of having prevalent invasive cancer, ii) is associated with a meaningful lead time to diagnosis, and iii) is identifiable by a systematic and scalable process in the population. Heuriskance aims to systematically detect cancer with clinically meaningful lead time to clinical diagnosis, minimize proportion of patients with advanced disease, and maximize treatment options leading to increases in lead time-adjusted 1-, 3- and eventually 5- year survival. A specific example of a heurisk for pancreatic cancer is glycemically defined new onset diabetes (GNOD) and the Early Detection Initiative (NCT04662879) an example of GNOD-based heuriskance. As heuriskance has no precedent, we provide i) a tiered risk stratification approach (Define-Enrich-Find), ii) metrics for choosing a heurisk, iii) success metrics for strategy and iv) Phases 1-5 for evaluating the strategy in retrospective and prospective studies. Like all current cancer therapies, heuriskance aims to iteratively improve survival from a fatal disease using a pragmatic, evidence-based systematic approach to its earlier detection. The concept of heuriskance is applied to pancreatic cancer but could be extended to other cancer types.

PURPOSE/OBJECTIVE:Pancreatic ductal adenocarcinoma (PDAC) disproportionately impacts Black and Latino/a communities, who are less likely to receive genetic counseling/testing referrals, hindering early cancer detection/prevention access. This study aims to determine the barriers/facilitators to PDAC genetics care/surveillance among Black and Latino/a populations. METHODS:This is a concurrent mixed-methods study that utilized electronic surveys and semi-structured focus groups/in-depth interviews (02/14/2022-12/21/2022). This was a volunteer sample of Black or Latino/a general participants with a personal or family history of PDAC and community leaders serving these groups. Participants discussed barriers/facilitators to PDAC cancer genetics care/surveillance. Health literacy, cancer worry, medical trust, and inherited cancer risk were assessed using electronic surveys. Discussions were recorded, transcribed, and analyzed using a content analysis approach. Chi-square tests, two-sample t-tests, and one-way analysis of variance were used to evaluate survey data using R v4.3.2. RESULTS:55 participants (n = 27 general participants, 28 leaders) completed surveys. 27 (49%) self-identified as Black and 23 (42%) as Latino/a. Leaders (74%) reported higher levels of perceived medical mistrust among their communities than general participants (Trust in Physician Scale mean/SD 29.9/4.2 vs. 38.4/5.2, p < 0.001; Medical Mistrust Index = 18.8/4.2 vs. 24.4/3.6; p < 0.001, respectively). General participants self-reported higher digital health seeking capabilities than leaders' perception of that skillset (p < 0.001). 24 of these participants completed a focus group/in-depth interview, emphasizing informed discussions with a trusted/established provider. CONCLUSIONS:Individuals impacted by PDAC are open to genetics care and desire resources to promote PDAC surveillance. It is also crucial that leaders and providers be engaged to facilitate access to this care.

Advances in spatial profiling have resulted in the generation of multi-omic atlases that span biological scales. In general, multiple workflows are required for image registration, coordinate registration, and spot deconvolution to integrate modalities. To improve the throughput of registration of multi-omic cohorts, we introduce PIVOT, a user-friendly and open-source interface for streamlined nonlinear registration. We demonstrate PIVOT's strengths through registration of three multi-omic datasets, and show comparison of its performance to existing workflows.

The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated nutrient salvaging and activation of multiple receptor tyrosine kinases for tumor maintenance, promoting resistance to KRAS∗-targeted therapy. Overall, our study provides a strong rationale for targeting the YAP-SDC1 axis to overcome resistance to KRAS∗ inhibition, thereby revealing promising therapeutic opportunities for improving the clinical outcome of patients with KRAS∗-mutated cancers.

BACKGROUND:Neoadjuvant chemotherapy has been used to downstage locally advanced ER+/HER2- breast cancer with low response rates. The optimal neoadjuvant regimen for this population is unknown. PATIENTS AND METHODS/METHODS:Between 2017 and 2022, 192 patients (ages 28-78) with stage II/III ER+/Her2- breast cancer at our institution were evaluated. Patients were divided into 4 groups based on the neoadjuvant chemotherapy regimen used (AC-T, TC, TAC, or other). The responses were categorized as complete (ypT0/is ypN0), partial, no response, or progressive disease. RESULTS:The choice of neoadjuvant chemotherapy was not predictive of pCR (P = .3864), even among those with more advanced nodal disease. No significant difference was noted in OS or IDFS at 24 or 48 months between the AC-T and TC groups. In the AC-T group (n = 130), 9 patients had a CR (6.98%), while no patients in TC group had a CR. Those who were premenopausal were more likely to achieve pCR compared to those postmenopausal. Race significantly impacted IDFS. CONCLUSIONS:In this single center study, we found no differences in IDFS or OS when comparing neoadjuvant TC to AC-T. The AC-T regimen group had a higher pCR rate of 6.98% compared to 0% in TC regimen group. Further exploration is needed to understand why non-white populations have inferior IDFS.

Although the severity of pathology in incoming college students has increased over the last decade, hospitalized students remain an under-researched group at risk for attrition, trauma, suicide, and disconnection with their universities. The present study sought to explore the experiences of hospitalization for college students at a large, public, Southwestern university through a lens of student retention theory, Self-Determination Theory (SDT), and institutional betrayal. Qualitative interviews were conducted with ten current or recently graduated students, hospitalized between Fall 2017 and Spring 2021, about their experiences with psychological services prior to hospitalization, the hospitalization process, the hospitalization itself, and post discharge. Interview participants had complex and nuanced experiences with hospitalization. Themes included neutral experiences with psychological services pre-hospitalization, trust/distrust, powerlessness, interpersonal connections, uncertainty, negative perceptions of the university, academic supports, and shifts in perspective. Future clinical and research implications are discussed.