PLK3

本文为转化医学网原创，转载请注明出处 作者：Rainbow 导读： 长链非编码RNA（lncRNA）在各种癌症特征的表观遗传调控中发挥关键作用，包括增殖、存活和通过与表观遗传修饰因子、转录因子/共激活因子或核糖核蛋白复合物相互作用的转移。 3月22日，上海交通大学冯海忠、李彦欣和昆明医科大学陈策实共同通讯在期刊《Molecular Cancer 》上在线发表题为“LINC00115 promotes chemoresistant breast cancer stem-like cell stemness and metastasis through SETDB1/PLK3/HIF1α signaling”的研究论文， 研究结果揭示了LINC00115作为乳腺癌干细胞的关键调控因子，并强调了靶向LINC00115和SETDB1作为化疗耐药性乳腺癌的潜在治疗策略。 https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01975-3 研究背景 01 癌症干细胞是癌细胞中的一个小群体，具有无限的增殖潜能和启动肿瘤克隆的能力。 累积的数据表明，癌症干细胞是各种癌症（包括乳腺癌）中治疗耐药、转移和复发的关键障碍，然而其潜在机制仍然不明确。 LINC00115在包括肺腺癌、视网膜母细胞瘤、前列腺癌、卵巢癌、乳腺癌和胶质瘤在内的多种癌症中上调。LINC00115是这些癌症的预后因子。LINC00115已被确认为功能性miRNA海绵，可调控miR-200s、miR-7和miR-489-3在癌症进展中的作用。已观察到TGF-β的上调介导神经胶质瘤干细胞的干性。研究表明，LINC00115通过上调SOX9并抑制Wnt/β-catenin通路，在卵巢癌干细胞中增强干性并抑制凋亡。 然而，LINC00115在治疗耐药性癌症干细胞中的作用仍未知。 HIF1α是通过促进乳腺癌干细胞表型来增强乳腺癌化疗耐药性和转移的通路的常见成分。HIF1α蛋白的稳定性和活性由一种包括蛋白激酶和蛋白/脂质磷酸酶的信号级联介导。GSK3β在氧依赖降解结构域内磷酸化HIF1α，导致HIF1α通过蛋白酶体途径增加降解。PLK3也可以通过直接与Ser576和Ser657上的HIF1α相互作用来磷酸化HIF1α，导致类似于GSK3β调控的HIF1α不稳定化。 SETDB1是一种H3K9甲基转移酶，负责组蛋白H3上的赖氨酸9甲基化，已被证明可以甲基化几种非组蛋白，如Akt。SETDB1依赖性甲基化在调节增殖、分化和细胞命运以及抑制癌症方面增强或阻碍各自的激酶活性。 目前尚不清楚SETDB1在乳腺癌化疗耐药和转移中对HIF1α信号传导的重要性。 研究发现 02 在这项研究中，研究人员对紫杉醇耐药的乳腺癌干细胞进行了全基因组lncRNA表达分析，并确定LINC00115是一个关键调节因子。结合RNA pull-down和质谱（MS）分析，研究人员展示了LINC00115作为一个支架lncRNA，通过 SETDB1/PLK3/HIF1α 信号传导调控乳腺癌干细胞的干性、化疗耐药性和转移。 研究发现揭示了治疗耐药乳腺癌干细胞的一个新调控因子。 研究结论 03 综上所述， 研究结果揭示了LINC00115作为乳腺癌干细胞的关键调控因子，并强调了靶向LINC00115和SETDB1作为化疗耐药性乳腺癌的潜在治疗策略。 参考资料： https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-01975-3 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 线上｜03月28日 ▶Twist全外显子组测序应用新篇章 🕓 上海｜03月28日-30日 ▶2024（第二届）合成生物学与生物医学健康大会参会指南公布！ 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

First-in-class macrocyclic ATR inhibitor, ATRN-119, on track to complete dose escalation and potentially generate human efficacy data in H2 2024 U.S. FDA cleared IND for APR-1051, a highly selective and potentially best-in-class oral WEE1 inhibitor; Company plans to initiate Phase 1 ACESOT-1051 clinical trial in H1 2024. $21.6 million in cash and cash equivalents as of December 31, 2023 Private placement financing in March 2024 raised upfront gross proceeds of approximately $16 million DOYLESTOWN, Pa., March 26, 2024 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (Nasdaq: APRE) (“Aprea”, or the “Company”), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, today reported financial results for the fourth quarter and full year ended December 31, 2023, and provided a business update. “Aprea had a very productive 2023 with significant progress across our diversified pipeline of synthetic lethality-based cancer therapeutics. We are pleased to continue this positive momentum in 2024 and focus on the execution on our programs towards successfully delivering potentially safer and more effective therapies for cancer patients,” said Oren Gilad, Ph.D., President and Chief Executive Officer of Aprea. “We continue to enroll and treat patients in the ongoing Phase 1/2a study of our novel macrocyclic ATR inhibitor, ATRN-119. ATRN-119 appears to be well tolerated with a manageable toxicity profile. Dose escalation will proceed throughout 2024 with potential for human efficacy data in the second half of the year. We are preparing to enter the clinic with our next generation inhibitor of WEE1 kinase, APR-1051, having received clearance from the FDA on our IND. Based on the unique characteristics of APR-1051 we believe it will be best in class.” Dr. Gilad continued “the closing of our recent private placement financing provides us with the capital to fund both of these lead programs through meaningful clinical milestones. I would like to thank our dedicated team, our academic collaborators, as well as existing and new investors who have supported our recent advancements. Our mission is to be a global leader in synthetic lethality and we see a great opportunity to help cancer patients in need and create value for our shareholders.” Key Business Updates and Potential Upcoming Key Milestones ATR inhibitor, ATRN-119, on track to complete monotherapy dose escalation end of the year; initial efficacy data expected in second half of 2024 ATRN-119 is a potent and highly selective first-in-class macrocyclic ATR inhibitor, designed to be used in patients with mutations in DDR-related genes. Cancers with mutation in DDR-related genes represent a high unmet medical need. Patients with DDR-related gene mutations have poor prognosis and, currently, have no effective therapies.In January 2023, enrollment commenced in an open-label Phase 1/2a clinical trial of ATRN-119 (study AR-276-010) as monotherapy in patients with advanced solid tumors having at least one mutation in a defined panel of DDR-related genes. In the ongoing monotherapy dose escalation phase (Part 1) of the trial, the primary endpoint is evaluating the tolerability and pharmacokinetics of continuous daily oral dosing of ATRN-119 using a 3+3 trial design in up to approximately 30 patients. A secondary endpoint is evaluating potential initial efficacy.An update from Part 1 of the trial was featured in a poster presentation at the AACR-NCI-EORTC International Conference in October 2023. As of January 2, 2024, 12 patients were enrolled to the first four cohorts of the Phase 1 escalation stage (50mg/day, 100mg/daily, 200mg/daily and 350mg/daily). ATRN-119 was found to be safe and well tolerated in all four cohorts, with no related adverse effects > grade 2. The most recent efficacy analysis conducted at that date shows that two patients achieved stable disease – one each in the 50 mg and 200 mg cohorts. Both these patients’ tumors have mutations that have been predicted to confer sensitivity to ATR inhibition.As of March 26, 2024 four clinical sites have been activated in the US. At completion of Part 1 of the study, the company anticipates identification of a recommended Phase 2 dose (RP2D) that will be used in a Phase 2a cohort expansion (Part 2) to test the tolerability and potential efficacy of ATRN-119 monotherapy in approximately 30 additional patients. The Phase 1 dose escalation is expected to be completed in 4Q 2024, and RP2D is to be determined in 1Q 2025. Enrollment in the Phase 2a cohort is expected to begin in 1Q 2025 with additional efficacy data expected in 3Q 2025.A more comprehensive dataset from Part 1 of the study has been accepted for presentation at the American Association of Cancer Research (AACR) annual meeting in April 2024.For more information, please refer to clinicaltrials.gov NCT04905914. Oral WEE1 inhibitor, APR-1051, expected to enter Phase 1 clinical trial in the first half of 2024 APR-1051 is a potent and selective small molecule that has the potential to avoid off target toxicity and achieve greater clinical activity than other WEE1 programs currently in development. Aprea is advancing APR-1051 as monotherapy in ovarian cancer with Cyclin E over expression. Cancers over expressing Cyclin E represent a high unmet medical need. Patients with Cyclin E over expression have poor prognosis and, currently, have no effective therapies.In March 2024, the U.S. FDA cleared the Investigational New Drug (IND) application (IND 169359) for APR-1051. Clearance of this IND will allow Aprea to initiate the Phase 1 ACESOT-1051 (A Multi-Center Evaluation of WEE1 Inhibitor in Patients with Advanced Solid Tumors, APR-1051) trial. This dose escalation trial will evaluate the safety, tolerability, and preliminary efficacy of APR-1051. Enrollment of the first patient is expected in H1 2024 with an update expected in the Q4 2024.Preclinical data on APR-1051 were presented in a poster at the AACR-NCI-EORTC International Conference in October 2023. The data highlighted the selectivity of APR-1051 with low off-target activity against PLK1, PLK2 and PLK3, a family of kinases that promote M phase entry, a critical phase in the cell cycle. APR-1051 showed potentially favorable PK properties and appears to cause lower inhibition of hERG, a potential indication of low cardiotoxicity. At doses and scheduling that suppress tumor growth, APR-1051 causes little anemia. The selectivity of APR-1051 may solve a long-standing problem with other WEE1 inhibitors. Recent studies indicate that PLK1 off-targeting partially counters the intracellular effects of WEE1 inhibition and could potentially contribute to the myelosuppression observed with other WEE1 inhibitors. Pipeline – lead candidate for a third synthetic lethality program to be selected in 2024 Aprea’s research and development team has identified a new target in synthetic lethality. Our discovery team is developing a series of molecules that are selective and potent against it.A lead molecule is expected to be declared in 2Q 2024.This program may provide clinically meaningful differences for cancer patients that currently have limited therapies. KOL Event Hosted a Key Opinion Leader (KOL) event on October 31, 2023, highlighting the Company’s portfolio of small molecules focused on Synthetic Lethality (SL) by targeting the DNA Damage Response (DDR) Pathways. The event featured Key Opinion Leaders Dr. Fiona Simpkins, Professor in the Division of Gynecology Oncology and Department of OB-GYN at the University of Pennsylvania, Dr. Timothy Yap, medical oncology physician-scientist and Professor at the University of Texas MD Anderson Cancer Center, Dr. Eric Brown, a consultant to Aprea and a Professor at the University of Pennsylvania and a member of the Abramson Family Cancer Research Institute, and Aprea’s Dr. Nadeem Mirza, Senior Medical Advisor. The speakers, along with the management team, provided an overview of the Company’s lead ATR inhibitor candidate, ATRN-119, and its WEE1 inhibitor candidate, APR-1051, and highlighted the addressable unmet clinical need and potential combination therapies using these programs. A replay of the event can be access on the Aprea corporate website here. Select Financial Results for the Fourth Quarter ended December 31, 2023 As of December 31, 2023, Aprea reported cash and cash equivalents of $21.6 million.For the quarter ended December 31, 2023, the Company reported an operating loss of $3.7 million, compared to an operating loss of $2.7 million in the fourth quarter of 2022.Research and Development (R&D) expenses were $2.0 million for the quarter ended December 31, 2023, compared to $0.5 million for the fourth quarter of 2022. The increase in R&D expense was primarily related to the Phase 1/2a clinical trial evaluating ATRN-119 which enrolled its first subject in Q1 2023 and IND enabling studies for APR-1051, the Company’s small molecule WEE1 inhibitor.General and Administrative (G&A) expenses were $1.6 million for the quarter ended December 31, 2023, compared to $2.1 million for the comparable period in 2022. The decrease in G&A expenses was primarily due to a decrease in personnel costs and insurance premiums.The Company reported a net loss of $3.4 million ($0.92 per basic share) on approximately 3.7 million weighted-average common shares outstanding for the quarter ended December 31, 2023, compared to a net loss of $2.4 million ($0.92 per basic share) on approximately 2.6 million weighted average common shares outstanding for the comparable period in 2022. Select Financial Results for the Year ended December 31, 2023 As of December 31, 2023, the Company reported cash and cash equivalents of $21.6 million compared to $28.8 million as of December 31, 2022. The Company believes its cash and cash equivalents as of December 31, 2023, combined with the upfront gross proceeds of approximately $16.0 million received from the Company’s private placement of common stock and warrants in March 2024, before deducting placement agent fees and offering costs of approximately $1.4 million, will be sufficient to meet its currently projected operating expenses and capital expenditure requirements into the third quarter of 2025.For the year ended December 31, 2023, the Company reported an operating loss of $15.5 million, compared to an operating loss of $113.4 million, which include $76.0 million for acquired in-process research and development, for the year ended December 31, 2022.Research and Development (R&D) expenses were $7.6 million for the year ended December 31, 2023, compared to $16.4 million for the year ended December 31, 2022. The decrease in R&D expense was primarily related to the close out of our clinical trials of eprenetapopt and APR-246, non-cash stock-based compensation from the acceleration of vesting of all outstanding stock options and restricted stock units in connection with the acquisition of Atrin Pharmaceuticals Inc. in 2022 and personnel costs primarily related to the close out of our research facility in Sweden during 2022.General and Administrative (G&A) expenses were $8.4 million for the year ended December 31, 2023, compared to $21.0 million for the year ended December 31, 2022. The decrease in G&A expenses was primarily due to a decrease in non-cash stock-based compensation from the acceleration of vesting of all outstanding stock options and restricted stock units in connection with the acquisition of Atrin Pharmaceuticals Inc. in 2022 and insurance premiums.The Company reported a net loss of $14.3 million ($3.95 per basic share) on approximately 3.6 million weighted-average common shares outstanding for the year ended December 31, 2023, compared to a net loss of $112.7 million ($67.99 per basic share) on approximately 1.7 million weighted average common shares outstanding for the comparable period in 2022. About Aprea Aprea Therapeutics, Inc. is a clinical-stage biopharmaceutical company headquartered in Doylestown, Pennsylvania, focused on precision oncology through synthetic lethality. The Company’s lead program is ATRN-119, a clinical-stage small molecule ATR inhibitor in development for solid tumor indications. Aprea has completed all IND enabling studies for its oral, small molecule WEE1 inhibitor, APR-1051, and recently received FDA clearance of its IND. For more information, please visit the company website at www.aprea.com. The Company may use, and intends to use, its investor relations website at https://ir.aprea.com/ as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD. Forward-Looking StatementCertain information contained in this press release includes “forward-looking statements”, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended related to our study analyses, clinical trials, regulatory submissions, and projected cash position. We may, in some cases use terms such as “future,” “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “targeting,” “confidence,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Our forward-looking statements are based on current beliefs and expectations of our management team and on information currently available to management that involve risks, potential changes in circumstances, assumptions, and uncertainties. All statements contained in this press release other than statements of historical fact are forward-looking statements, including statements regarding our ability to develop, commercialize, and achieve market acceptance of our current and planned products and services, our research and development efforts, including timing considerations and other matters regarding our business strategies, use of capital, results of operations and financial position, and plans and objectives for future operations. Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including, without limitation, risks related to the success, timing, and cost of our ongoing clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of initiation, pace of enrollment and completion of the trials (including our ability to fully fund our disclosed clinical trials, which assumes no material changes to our currently projected expenses), futility analyses, presentations at conferences and data reported in an abstract, and receipt of interim or preliminary results (including, without limitation, any preclinical results or data), which are not necessarily indicative of the final results of our ongoing clinical trials, our understanding of product candidates mechanisms of action and interpretation of preclinical and early clinical results from its clinical development programs, and the other risks, uncertainties, and other factors described under “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and elsewhere in the documents we file with the U.S. Securities and Exchange Commission. For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this press release. We undertake no obligation to update such forward-looking statements for any reason, except as required by law. Investor Contact: Mike MoyerLifeSci Advisorsmmoyer@lifesciadvisors.com Aprea Therapeutics, Inc. Consolidated Balance Sheets December 31, December 31, 2023 2022 Assets Current assets: Cash and cash equivalents $21,606,820 $28,786,647 Prepaid expenses and other current assets 914,275 1,366,859 Total current assets 22,521,095 30,153,506 Property and equipment, net 88,362 2,321 Restricted cash 40,717 — Total assets $22,650,174 $30,155,827 Liabilities and Stockholders’ Equity Current liabilities: Accounts payable $1,670,369 $842,754 Accrued expenses 2,186,262 2,358,332 Deferred revenue 528,974 — Total current liabilities 4,385,605 3,201,086 Total liabilities 4,385,605 3,201,086 Commitments and contingencies Series A convertible preferred stock, $0.001 par value, 40,000,000 shares authorized; 56,227 shares issued and outstanding at December 31, 2023 and December 31, 2022, respectively. 1,311,063 1,311,063 Stockholders’ equity: Common stock, $0.001 par value, 400,000,000 shares authorized, 3,736,673 and 2,655,269 shares issued and outstanding at December 31, 2023 and December 31, 2022, respectively. 3,736 2,655 Additional paid-in capital 335,644,204 330,060,836 Accumulated other comprehensive loss (10,611,273) (10,623,408) Accumulated deficit (308,083,161) (293,796,405) Total stockholders’ equity 16,953,506 25,643,678 Total liabilities and stockholders' equity $22,650,174 $30,155,827 Aprea Therapeutics, Inc. Consolidated Statements of Operations and Comprehensive Loss Three Months Ended December 31, Year Ended December 31, 2023 2022 2023 2022 (Unaudited) Grant revenue $14,075 $— $583,231 $— Operating expenses: Research and development 2,045,689 531,406 7,627,491 16,402,273 General and administrative 1,643,315 2,120,222 8,427,703 20,969,771 Acquired in-process research and development — — — 76,020,184 Total operating expenses 3,689,004 2,651,628 16,055,194 113,392,228 Loss from operations (3,674,929) (2,651,628) (15,471,963) (113,392,228) Other income: Interest income, net 310,287 243,082 1,224,133 448,667 Foreign currency gain (loss) (78,612) (33,596) (38,926) 281,534 Total other income 231,675 209,486 1,185,207 730,201 Net loss $(3,443,254) $(2,442,142) $(14,286,756) $(112,662,027) Other comprehensive gain (loss): Foreign currency translation 24,601 (382,763) 12,135 (264,452) Total comprehensive loss (3,418,653) (2,824,905) (14,274,621) (112,926,479) Net loss per share attributable to common stockholders, basic and diluted $(0.92) $(0.92) $(3.95) $(67.99) Weighted-average common shares outstanding, basic and diluted 3,736,673 2,649,349 3,617,607 1,657,055

DOYLESTOWN, Pa., Jan. 04, 2024 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (Nasdaq: APRE) (“Aprea”, or the “Company”), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, today provided a corporate update highlighting recent developments and plans for advancement of its pipeline of DNA Damage Response (DDR) anti-cancer agents in 2024. “Having made substantial progress over the past twelve months, we are well positioned for ongoing success in 2024 as we execute on our mission to be a global leader in synthetic lethality,” said Dr. Oren Gilad, President and CEO of Aprea. “We continue to advance towards achieving our milestones in the ongoing dose-escalation Phase 1 study of our novel macrocyclic ATR inhibitor, ATRN-119, and are finalizing submission of the IND for our next-generation, best-in-class WEE1 inhibitor, APR-1051. This IND is supported by a compelling pre-clinical package showing highly potent and selective anti-tumor activity, limited off-target effects, and favorable pharmacokinetics.” Update on Phase 1/2a Ongoing Trial of ATR Program, ATRN-119 Enrollment of patients continues in the dose escalation portion of the Phase 1/2a clinical trial (study AR-276-01) evaluating ATRN-119 in patients with advanced solid tumors having mutations in defined DDR-related genes. The primary objective of the Phase 1 part of this trial is evaluating the tolerability and pharmacokinetics of ATRN-119 when administered orally on a continuous, once-daily schedule. The daily dosing of ATRN-119 provides continuous ATR inhibition that may be preferable to intermittent dosing for both efficacy and safety, potentially supporting an important competitive advantage over the current class of ATR inhibitors. The secondary objective is the evaluation of antitumor efficacy. The most recent analysis of the data cut (January 2, 2024) shows that two patients have achieved stable disease – one each in the 50 mg and 200 mg cohorts. Importantly, both these patients’ tumors have mutations that have been predicted to confer sensitivity to ATR inhibition. The dose-limiting toxicity period for cohort 4 (350 mg) has been completed. The most recent patient with stable disease from cohort 3 (200mg), with a history of five prior lines of therapy is at approximately four months of treatment duration with ATRN-119, and, following clearance of the 350 mg cohort, is expected to be increased from 200 mg to 350 mg daily, as per the dose escalation trial protocol. ATRN-119 is being developed as the first and only macrocyclic ATR inhibitor. Macrocycles restrict the number of conformations that a molecule can form, potentially resulting in increased potency and increased selectivity. These properties are expected to permit higher dosing that is potentially more effective with increased tolerability and decreased off-target activity. The company plans to amend the design of the ongoing study beyond the current 800 mg high-dose cohort to incorporate additional higher dose groups. Upon the addition of the higher dose cohorts, Aprea expects to determine the recommended Phase 2 dose (RP2D) in the second half of 2024. Following dose escalation, the Phase 2a dose expansion part of the study may include patients with NSCLC, breast, colorectal, prostate, and ovarian cancers with selected genetic mutations. Importantly, the potential for reduced hematologic toxicity from ATRN-119 suggests it may be an ideal DDR inhibitor for novel combination therapies. These potential combinations include ATRN-119 with PARP inhibitors, WEE1 inhibitors, and Antibody-Drug Conjugates (ADCs). The latter of these possibilities could provide a significant breakthrough for the use of ADCs linked to standard chemotherapies, as these promising biopharmaceuticals are often constrained by aberrant drug release and dose-limiting toxicities. Combination with ATRN-119 would potentially amplify the DNA-damaging effects of these ADCs in the targeted tumor cells, thus affording greater efficacy at lower ADC doses. A more comprehensive dataset from the Phase 1 part of AR-276-01 will be submitted for presentation at a medical meeting in the first half of 2024. For more information, please refer to clinicaltrials.gov NCT04905914. Investigational New Drug (IND) for WEE1 Program, APR-1051 Aprea completed IND-enabling studies and is finalizing the submission of the IND application with the FDA to begin clinical trials of APR-1051 in the first half of the year. APR-1051 is being developed as a next-generation, potential best-in-class inhibitor of WEE1 kinase with the following properties: APR-1051 has a different molecular structure from all other WEE1 inhibitors currently in development with improved selectivity for the target. The improved properties of APR-1051 relative to the other WEE1 inhibitors include its limited effects on red blood cell counts, hERG inhibition, and body weight loss in pre-clinical studies. The selectivity of APR-1051 may solve a long-standing problem with WEE1 inhibitors. Preclinical studies have shown that APR-1051 is site-specific to WEE1 and does not significantly inhibit the PLK1, PLK2, and PLK3 family of kinases, potentially increasing the cancer-killing effects of WEE1i inhibition and reducing hematological toxicity caused by PLK off-targeting. PLK off-target activity has been a challenge for other WEE1 inhibitors. Recent studies indicate that PLK1 off-targeting partially counters the intracellular effects of WEE1 inhibition and could potentially contribute to the myelosuppression observed with other WEE1 inhibitors.Specific genetic mutations driving patient selection have been identified. The company expects to receive FDA clearance on the IND during Q1 2024. Clinical development is in line with FDA requirements for a dose escalation trial to evaluate safety and pharmacokinetics. Leading institutions and a Principal Investigator have been identified for the trial. Company to Participate in 2024 Corporate Access Event Aprea will be hosting institutional investor and business development meetings at the Annual Corporate Access Event in San Francisco, hosted by our investor relations firm LifeSci Partners. Management will be available for meetings on Wednesday, January 10, 2024. To schedule a meeting, interested parties can register here or send an email to access@lifesciadvisors.com. About ApreaAprea Therapeutics, Inc. is a clinical-stage biopharmaceutical company headquartered in Doylestown, Pennsylvania, focused on precision oncology through synthetic lethality. The Company’s lead program is ATRN-119, a clinical-stage small molecule ATR inhibitor in development for solid tumor indications. Aprea completed all IND enabling studies and is moving towards the submission of an oral, small molecule WEE1 inhibitor, APR-1051. For more information, please visit the company website at www.aprea.com. The Company may use, and intends to use, its investor relations website at https://ir.aprea.com/ as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD. Forward-Looking Statement Certain information contained in this press release includes “forward-looking statements”, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended related to our study analyses, clinical trials, regulatory submissions, and projected cash position. We may, in some cases use terms such as “future,” “predicts,” “believes,” “potential,” “continue,” “anticipates,” “estimates,” “expects,” “plans,” “intends,” “targeting,” “confidence,” “may,” “could,” “might,” “likely,” “will,” “should” or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Our forward-looking statements are based on current beliefs and expectations of our management team and on information currently available to management that involve risks, potential changes in circumstances, assumptions, and uncertainties. All statements contained in this press release other than statements of historical fact are forward-looking statements, including statements regarding our ability to develop, commercialize, and achieve market acceptance of our current and planned products and services, our research and development efforts, including timing considerations and other matters regarding our business strategies, use of capital, results of operations and financial position, and plans and objectives for future operations. Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including, without limitation, risks related to the success, timing, and cost of our ongoing clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of initiation, pace of enrollment and completion of the trials, futility analyses, presentations at conferences and data reported in an abstract, and receipt of interim or preliminary results (including, without limitation, any preclinical results or data), which are not necessarily indicative of the final results of our ongoing clinical trials, and the other risks, uncertainties, and other factors described under “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and elsewhere in the documents we file with the U.S. Securities and Exchange Commission. For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this press release. We undertake no obligation to update such forward-looking statements for any reason, except as required by law. Investor Contact: Mike MoyerLifeSci Advisorsmmoyer@lifesciadvisors.com