Susan Thompson Buffett Foundation

Pancreatic DuctalAdenocarcinoma (PDAC) is one of the most lethalmalignancies, with limited treatment options. Altered lipid metabolism,including dysregulated eicosanoid pathways, plays a role in PDAC progressionand therapy resistance. In this study, we investigated the impactof a treatment with polymeric hydroxychloroquine (PCQ), a novel macromolecularderivative of hydroxychloroquine (HCQ), on tumor lipid metabolismin a syngeneic mouse model of PDAC. Using a validated LC-MS/MS method,we quantified 72 eicosanoids in tumors to assess the metabolic changesinduced by PCQ and HCQ treatment. Our findings revealed significantPCQ-mediated downregulation of multiple protumorigenic eicosanoids,including PGD2, PGJ2, LTE4, LTB4, and HETEs, and upregulation of antitumorresolvins. This was further confirmed by Partial Least Squares DiscriminantAnalysis (PLS-DA) and heatmap analysis. The parent compound HCQ showedminimal impact on eicosanoid concentrations in the tumors, with nosignificant alterations at 24-h and modulation of only six eicosanoidsdownregulated at 72-h post treatment. Overall, our data highlighta novel role of PCQ in modulating tumor lipid metabolism, suggestinga unique mechanism of action and its potential as an adjuvant agentin the therapy of PDAC.

Prostate cancer (PCa) is the second most common and a leading cause of cancer-related deaths among men. Current screening methods lack precision in distinguishing aggressive cases, emphasizing a need for tissue-based biomarkers. Although Golgi disorganization, ER stress, and elevated high-mannose (Man) glycoproteins (e.g., Integrin αv, key metastatic player) are recognized features of metastatic prostate tumors, their interrelationships remain unexplored. It is observed that the growth of primary prostate tumors is linked to an increase in endoplasmic reticulum (ER)-plasma membrane (PM) junctions signaling, mediated by STIM1 and ORP5. However, transition to lymph node and tissue metastasis is associated with their downregulation, loss of ER-PM communications, significant Golgi dispersal, and rapid conversion of high-Man glycans in the Golgi to atypical MGAT5-modified sugars that facilitate Integrin αv clustering at the PM via Galectin-3 binding. Golgi dispersal is associated with increased organelle volume and surface area to accommodate heightened trafficking and processing. These findings position STIM1 and ORP5 as biomarkers of aggressive PCa and show that high-Man enrichment is not due to defective maturation but reflects a glycan pool that cancer cells actively utilize, suggesting that the concept of ER stress response in PCa should be redefined to include Golgi reorganization and altered ER-PM junctions.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain provide recommendations for the comprehensive management of pain in patients with cancer. This article will focus on methods for screening for pain, safe and appropriate prescription of opioid and miscellaneous analgesics, and the optimization of nonpharmacologic interventions including integrative and interventional strategies for treatment of cancer-related pain. Additionally, the NCCN Guidelines discuss methods for the safe reduction of opioids when appropriate, as well as techniques for encouraging the judicious use of opioids. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional issues that are not covered here, including management of pain during a pain crisis, management of procedure-related pain and anxiety, pain management for cancer survivors, and the use of nonopioid and adjuvant analgesics for cancer-related pain.

Abstract Introduction. Metastasis is the major cause of mortality in patients with solid tumors. Our group has identified precision therapeutic inhibitors of cell motility and shown their ability to prevent metastasis. In striving to move novel first-in-class therapy into humans, it is important to identify biomarkers of therapeutic efficacy. As β1 and β5 integrins mediate prostate cancer cell migration, they are strong biomarker candidates. While our novel anti-motility agent, KBU2046, inhibits cell motility, its effects on β1 and β5 integrin expression and dynamics are not fully understood. We, therefore, investigated the impact of KBU2046 on β1 and β5 integrin patterns in cells and their potential as predictive biomarkers of therapeutic response. Experimental procedures. Initial screening studies consisted of orthogonal protein expression measures, including mass spectrometry and Western blot-based analytics, in the context of time- and concentration-based treatment anti-motility therapeutics. This was then followed by immunofluorescence (IF) analysis by confocal microscopy of a panel of human prostate primary and metastatic cells, examining patterns of expression under conditions of static as well as synchronized cell attachment. Results. Evaluation of the proteome through bioinformatic analytics identified changes in cell adhesion proteins as high-potential biomarkers. From this, we specifically investigated the dynamics of β1 and β5 integrins in response to antimotility treatment with KBU2046. In this manner, treatment induced significant alterations in cell morphology. This was associated with a dynamic, time-dependent redistribution of β1 and β5 integrins. The pattern of this change demonstrates disruption in normal integrin trafficking and supports a basis for disruption of normal integrin function. These findings provide orthogonal support for the established role of KBU2046 in inhibiting cell motility and identify β1 and β5 integrin expression patterns as high-potential biomarkers of therapeutic efficacy for anti-motility agents. Conclusions. Our investigation reveals that treatment with KBU2046 induces significant changes in the dynamics of β1 and β5 integrins in prostate cancer cells, disrupting their normal function and trafficking. Using IF and protein expression analyses, we identified β1 and β5 integrins as potential biomarkers indicative of therapeutic efficacy in response to anti-motility treatment. These findings underscore the significance of β1 and β5 integrin expression patterns as key indicators for assessing the effectiveness of future anti-motility strategies. Further investigation of these biomarkers in clinical settings could offer valuable insights to inform therapeutic decisions in the treatment of prostate cancer. Citation Format: Weining Chen, Nicholas Woods, Henry Chun Hin Law, Fangfang Qiao, Raymond C. Bergan. The role of β1 and β5 integrins as biomarkers in anti-motility therapy treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2364.

Abstract The identification of Thalidomide, Lenalidomide, and Pomalidomide as Cereblon (CRBN) binders spurred the development of proteolysis-targeting chimeras (PROTACs). PROTACs with CRBN-binding moieties are heterobifunctional molecules that form a ternary complex with CRBN, which recruits the CUL4-DDB1 ubiquitin ligase protein complex, and a protein of interest (POI) and targets it for degradation. Despite numerous ongoing efforts, the structure-based design of PROTACs remains elusive. The current approach relies on the synthesis of a PROTAC library and screening the library in the chosen assay format to identify viable hits. Here, we propose a viability-based phenotypic screening system using HCT116 wild type (WT) POI knock-out (POI-/-) and CRBN knock-out (CRBN-/-) cells to identify PROTACs that display activity in both a POI and CRBN-dependent manner. For this study, we selected MAP3K1, an oncogenic signaling activator, as our POI and conjugated an ATP-competitive MAP3K1 inhibitor with thalidomide using various linkers to generate the library. The library was subjected to a 3-day viability screen using the above WT, MAP3K1-/-, and CRBN-/- cell lines. The screen identified 50-008 as a hit that selectively inhibited the viability of the WT cells but not MAP3K1-/- or CRBN-/- cells. 50-008 was chemically validated in a colorectal cancer cell line and organoid model by making single changes that affect either CRBN binding, MAP3K1 binding, or the linker. Follow-up studies showed that 50-008 inhibits cancer cell proliferation, induces apoptosis, and an S-phase cell cycle arrest in a CRBN and MAP3K1-dependent manner. Furthermore, A Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) screen of 50-008 across ∼900 cancer cell lines identified 267 sensitive cancer cell lines (IC50 < 0.1μM), including luminal B breast cancer cell line T47D and 131 resistant cancer cell lines (IC50 > 10 μM). Mechanistic studies in T47D cells demonstrated that 50-008 degrades MAP3K1 and modulates the activation of key downstream effectors, such as ERK and IKKβ. Citation Format: Lelisse T. Umeta, Jayapal R. Mallareddy, Sarbjit Singh, Smitha Kizhake, Lidia Boghean, Amritha Kizhake, Suchita Vishwakarma, Katelyn L. O’Neill, Lisa Humphrey-Brattain, Adrian Black, Xu Luo, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Amarnath Natarajan. A phenotypic screening method identifies a potent anti-cancer PROTAC targeting MAP3K1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7023.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a "watch-and-wait" nonoperative management approach for clinical complete responders to neoadjuvant therapy.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.