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Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. Significance: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

Triple Negative Breast Cancer (TNBC), characterized by low/absent expression of the estrogen receptor and the HER2 growth factor receptor, has high rates of metastasis and an overall poor prognosis largely due to a lack of targeted therapeutic options. The Eyes absent (Eya) family of proteins are transcriptional cofactors with both intrinsic tyrosine phosphatase and associated serine/threonine phosphatase activities. In addition to developmental functions, Eyas have been shown to play a role in promoting many hallmarks of cancer. Published work from our laboratory demonstrated that Eya3 is capable of upregulating expression of PD-L1 in TNBC tumors thereby suppressing anti-tumor CD8+ T-cell responses, and preliminary data suggests that Eya3 may also regulate the expression of various cytokines in this context. In tumor cells, innate immune signaling pathways, such as NF-kB, have been shown to promote tumor progression, immune evasion, and metastasis in many distinct tumor types. We hypothesize that, in addition to regulating CD8+ T-cell responses, Eya3 regulates innate immune signaling in TNBC cells to facilitate enhanced primary tumor growth and metastasis. Preliminary findings suggest that Eya3 is a key mediator of tumor progression and metastasis in TNBC and a strong regulator of NF-kB signaling in this context. Further exploration is warranted to determine the mechanism through which Eya3 regulates these phenotypes, whether Eya3-mediated NF-kB activation is a major contributor to the pro-metastatic phenotype of Eya3, and whether Eya3 could serve as a therapeutic target for preventing or treating disseminated TNBC. Citation Format: Connor J. Hughes, Rebecca Mallo, Kaiah Fields, Hengbo Zhou, Annika Gustafson, Deguang Kong, Jill Slansky, Rui Zhao, Heide L. Ford. Investigating the role of Eya3 in the regulation of NF-kB signaling and tumor progression in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2440.

e19153 Background: Several retrospective studies suggest patients enrolled in clinical trials have more end-of-life health care utilization (EOLHCU). This is particularly concerning for phase I clinical trial participants who are known to have therapeutic misconceptions about the purpose and benefits of phase I clinical trial participation. Methods: We identified all phase I participants at the Seattle Cancer Care Alliance (SCCA) with thoracic, head and neck cancers (THNC) who died between July 1, 2014 and June 30, 2018(P1C). We compared them to 139 randomly selected THNC patients who died within the same time period without phase I study participation (NP1C). Patient records were abstracted from the electronic health record (and Epic Care Everywhere if patients received EOL care outside of SCCA). A chi-square test was used to compare categorial variables and t-tests were used for numerical variables. Results: 67 P1C patients were identified; 3 patients had no outside records at the end of life and were removed from the database. No statistically significant differences in gender, ethnicity, marital status, or form of insurance were found between the two groups. P1C patients were younger (median age of 62 (interquartile range (IQR) 55-69) vs. 66 (IQR 59-72), p=0.008) and had more lines of therapy from diagnosis until death (median 4 (IQR 1-3) vs. 2 (IQR 1-3), p=

229 Background: When asked, many people wish to die at home. Yet, more than one third of cancer patients with poor prognosis die in hospital. Enrollment in hospice care is associated with reduced receipt of high-intensity care toward the end of life. Hospice is palliative care tailored to patients in the last 6 months of life. The ability to collect, organize, analyze and report documented Goals of Care (GOC) conversation data and the relationship to hospice enrollment is challenging. Seattle Cancer Care Alliance (SCCA) created a process to establish a sample baseline of documented GOC discussions, the healthcare setting in which they took place, and how this relates to hospice enrollment. Methods: We selected a sample of 50 decedent charts. Patients were verified as period of 6 months from date of death, documenting provider type, care setting that documented discussion took place and chart search terms. Results: Our sample consisted of 50 adult solid tumor cancer patients who died between March-May 2018. Using an SCCA created GOC discussion definition adapted from Ariadne Labs Serious Illness Care program, we found that 52% of patients had a GOC discussion in the last 6 months of life and of these, 92% discussed hospice with a provider, 77% received a hospice referral and 62% enrolled in hospice. 48% of our decedent sample did not have a GOC discussion. 46% had a hospice discussion of whom 100% enrolled in hospice. 46% received a hospice referral. 54% of patients did not discuss hospice of whom 30% enrolled in hospice. In looking at which providers talked with patients about hospice and in what care setting, we found that 44% discussed hospice with outpatient medical oncologist, 10% discussed hospice with an outpatient provider, 16% had a discussion while inpatient, and 30% had no hospice discussion at all. Conclusions: The majority of GOC discussions happened in the outpatient setting with medical oncologists. Many patients never had a discussion about hospice with their provider. Patients were most likely to enroll in hospice when it was specifically discussed, regardless of whether a GOC discussion took place.

9 Background: For commercial insurance plans, there is often a requirement to obtain prior-authorization for specific services. Prior-authorization though intended to ensure medical necessity, can cause significant delays in patient care and create an unnecessary administrative burden. It often leads to undue anxiety in patients, dissatisfaction among providers and substantial waste in the system. To increase our efficiency and improve patient and provider experience, we partnered with one of our region’s largest commercial payors to eliminate prior-authorization. Methods: A Lean Six-sigma DMAIC approach was adopted: Define- created a process map. Measure- calculated baseline for prior-authorization denials. Analyze- conducted retrospective analysis to identify areas to improve. Improve- conducted provider training for appropriate imaging guidelines. Control- established internal auditing to check provider compliance. Results: At SCCA, we found that 94.8% of prior-authorizations were approved instantly or after providing more documentation, thus prior-authorization did not add value. Moreover, 2.15% were approved after peer-to-peer review that involves significant administrative burden and delay in care. Only 3% prior-authorizations did not meet medical necessity criteria, major reasons being- PET/CT and CT CAP ordered in combination, or PET/CT ordered without clear justification. 2.46% prior-authorizations led to a patient receiving a letter of denial. SCCA and the payor agreed to eliminate prior-authorizations for all imaging (except PET and PET/CT). This required all ordering providers to attest to completion of training on the NCCN Imaging Appropriate Use Criteria. In addition, a quarterly internal audit was put in place to check provider compliance to NCCN guidelines for ordering Imaging tests. SCCA achieved a 100% provider training completion rate and 100% provider compliance to NCCN guidelines in the first two internal audits. Conclusions: A strong partnership and shared vision with a payor enabled us to eliminate wasteful prior-authorizations. Our high training completion rate and compliance rate implies strong support from our providers and leadership to provide value-based care to our patients.

Background: Colorectal cancer (CRC) ranks third in new cases and cancer deaths in the U.S. annually. The current front-line treatments for metastatic CRC (mCRC) are ineffective for an appreciable proportion of patients and induce significant toxicities. Thus, there is an urgent need for the development of new therapeutic strategies. Translation is a novel, underutilized target for cancer therapeutics. Eukaryotic elongation factor 2 (eEF2) is often overexpressed in CRC, causing upregulation of translation, upon which CRC may be dependent. Therefore, it may be possible to differentially target CRC cells by inhibiting translation. SVC112 is a novel inhibitor of translation and the parent molecule of SVC112 has been shown to lock eEF2 onto the ribosome. As such, this agent may be effective against mCRC by blocking translation of key oncogenes such as c-myc, which is overexpressed in mCRC. Methods: Forty-four CRC cell lines were exposed to SVC112 in vitro and CellTiter Glo ATP quantification was used to determine sensitivity or resistance based on IC50 values. Select sensitive and resistant cell lines were further validated with clonogenic assays to evaluate for sustained response. Immunoblotting was performed to assess levels of c-myc, survivin, and cyclin D1 in response to treatment with SVC112. Amino acid incorporation was measured using the Click-IT AHA kit protocol. eEF2 mRNA levels were ascertained from RNA seq data while cell cycle effects were determined by flow cytometry. Two cell line xenografts deemed to be sensitive based on IC50 values were treated in vivo with SVC112. Results: A subset of CRC cell lines were found to be sensitive to SVC112 in vitro, and notably, there was a trend towards increased eEF2 expression and greater responsiveness to SVC112. In sensitive cell lines, c-myc was downregulated by SVC112 in a dose-dependent manner whereas in resistant cell lines c-myc levels were not affected. Moreover, SVC112 caused a reduction of amino acid incorporation in sensitive cell lines compared to resistant cell lines. Likewise, the sensitive cell lines exhibited dose-dependent effects on the cell cycle with SVC112 whereas resistant cell lines did not. SVC112 demonstrates synergy with 5-FU in sensitive cell lines, while in the models and dosing conditions tested thus far, SVC112 has not demonstrated single agent efficacy in vivo. Conclusions: SVC112 demonstrates anticancer effects in a subset of CRC cell lines, indicating that translation machinery may be an effective druggable target in CRC. There is an apparent correlation between EF2 levels and sensitivity, which could be used as a selection strategy for sensitive tumors moving forward. SVC112’s ability to decrease amino acid incorporation and deplete c-myc in sensitive cell lines substantiates the proposed mechanism of action. Further experiments are needed to investigate the mechanism of resistance and whether this is related to anti-eEF2 exposure or a mechanism unrelated to eEF2 escape. Further analysis of SVC112 ribosomal engagement is ongoing. SVC112 has demonstrated synergistic effects with 5-FU, a standard chemotherapeutic for CRC, indicating its potential efficacy in combination therapy. Currently, PK analysis is under way and alternative dosing regimens in vivo may be warranted. Citation Format: Kelli M. Robertson, Annika L. Gustafson, John J. Tentler, Stacey M. Bagby, Capasso Anna, Peter J. Klauck, Todd M. Pitts, Jihye Kim, Aik Choon Tan, Tin Tin Su, S. Gail Eckhardt. Exploiting translation inhibition: antitumor efficacy of SVC112 in preclinical models of colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B051.