On April 12, 2021 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported it will report financial results for the first quarter 2021 after market close on Thursday, May 6, 2021 (Press release, Guardant Health, APR 12, 2021, View Source [SID1234577935]). Company management will be webcasting a corresponding conference call beginning at 1:30 p.m. Pacific Time / 4:30 p.m. Eastern Time.

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Live audio of the webcast will be available on the "Investors" section of the company website at: www.guardanthealth.com. The webcast will be archived and available for replay after the event.

On April 12, 2021 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers, reported a clinical collaboration agreement with GlaxoSmithKline ("GSK") in which Zentalis will evaluate the combination of ZN-c3, Zentalis’ oral WEE1 inhibitor product candidate, and ZEJULA (niraparib), GSK’s poly (ADP-ribose) polymerase (PARP) inhibitor, in patients with advanced epithelial ovarian cancer (Press release, Zentalis Pharmaceuticals, APR 12, 2021, View Source [SID1234643100]). Zentalis is currently conducting clinical studies with ZN-c3 both as a monotherapy and in combination with certain standard of care therapies.

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"This clinical collaboration and supply agreement with GSK allows us to investigate the broader potential of our WEE1 inhibitor when used as part of a combination treatment with niraparib, a PARP inhibitor," commented Dr. Anthony Sun, Chairman and Chief Executive Officer of Zentalis Pharmaceuticals. "As demonstrated in our preclinical studies, ZN-c3 is designed to have significant advantages over other investigational WEE1 inhibitor therapies. We believe this combination has the potential to meaningfully improve the outcomes for patients with ovarian cancer."

PARP inhibitors prevent DNA damage repair in cancer cells. Similar to PARP, WEE1 plays a role in cellular regulation and repair, allowing cells with DNA damage to repair and survive. Inhibition of WEE1 causes dysregulation of DNA replication and subsequently induces apoptosis. Based on these complementary mechanisms of action, the use of WEE1 and PARP inhibitors could potentially have synergistic anti-tumor activity.

More than 300,000 women worldwide are diagnosed with ovarian cancer each year, leading to over 180,000 fatalities1. While substantial progress has been made in the treatment of this disease, there is an urgency to address the remaining unmet need through the development of innovative combination treatments.

Under the terms of the non-exclusive collaboration, Zentalis is responsible for conducting the study with GSK providing all required doses of niraparib. Zentalis maintains full ownership of ZN-c3.

1www.cancerresearch.org

About ZN-c3

ZN-c3 is an oral inhibitor of WEE1 in development for the treatment of advanced solid tumors. The inhibition of WEE1, a DNA damage response protein, aims to generate sufficient DNA damage in cancer cells, causing cell death, thereby preventing tumor growth and potentially causing tumor regression. Zentalis is currently conducting a Phase 1/2 clinical trial in patients with advanced solid tumors and reported initial data from the Phase 1 portion at the AACR (Free AACR Whitepaper) Annual Meeting 2021. In addition, the Company is also conducting a Phase 1b trial evaluating ZN-c3 in combination with chemotherapy in patients with advanced ovarian cancer, with plans to initiate a Phase 1/2 trial in combination with GSK’s niraparib in patients with advanced ovarian cancer, a Phase 1/2 trial in combination with chemotherapy in osteosarcoma and a Phase 2 trial investigating ZN-c3 as a monotherapy in patients with uterine serous carcinoma in 2021.

About ZEJULA (niraparib)

GSK’s ZEJULA (niraparib) is an FDA and EMA-approved oral, once-daily poly (ADP-ribose) polymerase inhibitor that is currently being evaluated in multiple pivotal trials. GSK is building a robust niraparib clinical development programme by assessing activity across multiple tumour types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development programme for niraparib includes several combination studies, including Phase III studies in ovarian and non-ovarian indications.

On April 12, 2021 Helix BioPharma Corp. (TSX, FSE: HBP) ("Helix" or the "Company"), an immunooncology company developing innovative drug candidates for the prevention and treatment of cancer, reported that it has received conditional approval from the Toronto Stock Exchange (the "TSX") to extend the exercise period of a total of 2,837,000 outstanding common share purchase warrants (the "Warrants"), all of which are held by arm’s length parties (Press release, Helix BioPharma, APR 12, 2021, View Source [SID1234577903]). The Warrants were issued pursuant to a private placement of the Company completed on April 27, 2016 and represent approximately 2.0% of the Company’s issued and outstanding common shares.

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Each Warrant currently entitles the holder to purchase one common share of the Company at an exercise price of $1.98 at any time until April 27, 2021. Subject to TSX approval, the expiry date of the Warrants will be extended by two years to April 26, 2023. The exercise price of the Warrants will remain unchanged at $1.98. If approved by the TSX, the effective date of the amendment will be April 27, 2021.

On April 12, 2021 Molecular Templates, Inc. (Nasdaq: MTEM, "Molecular Templates," or "MTEM"), a clinical-stage biopharmaceutical company focused on the discovery and development of proprietary targeted biologic therapeutics, engineered toxin bodies (ETBs),reported that three posters featuring data on its pipeline programs and technology platform will be presented at the AACR (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Molecular Templates, APR 12, 2021, View Source [SID1234577919]).

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Title: Phase 1 Study of the Novel Immunotoxin MT-5111 in Patients with HER2+ Tumors
Authors: Zev A. Wainberg, MD; Monica M. Mita, MD; Minal A. Barve, MD; Erika P. Hamilton, MD; Andrew J. Brenner, MD, PhD; Frances Valdes, MD; Daniel Ahn, DO; Joleen Hubbard, MD; Jason Starr, DO; Christine Burnett, PhD; Joshua Pelham; Eric T. Williams, PhD; Aimee Iberg, PhD; Thomas Strack, MD; Andrés Machado Sandri, MD; Brian A. Van Tine, MD, PhD
Abstract # CT130
This poster summarizes results from a data cut in December 2020 for an ongoing Phase 1, first in human, open-label, dose escalation and expansion study of MT-5111 in subjects with HER2+ solid tumors. MT-5111 has a novel mechanism of action that may not be subject to resistance mechanisms that exist for current HER2 therapies, binds a distinct epitope on HER2 that allows for potential combination with trastuzumab-based therapies, and, at 55kDa, is significantly smaller than other HER2 antibody or ADC therapies. As of the data cut in December 2020, 16 study subjects had been treated in the 3+3 cohort escalation. The cancer types included biliary tract (n=6), breast (n=6), pancreatic (n=2), gastric (n=1), and colon (n=1). Results to date show that MT-5111 has been well tolerated at escalated doses up to Cohort 5 (4.5 µg/kg), which allowed for the progression to Cohort 6 (6.75 µg/kg). There have not been any dose limiting toxicities nor any signs of cardiotoxicity to date, and the MTD has not been reached. Pharmacokinetic data for the first 5 cohorts matched simulations based on non-human primate studies. Exposures at 4.5 µg/kg have reached approximately 5x the IC 50 of HER2-expressing cell lines.

Three patients experienced stable disease as best response per RECIST 1.1 criteria (1 pancreatic at 4.5 µg//kg, 1 breast at 2 µg//kg, 1 biliary tract at 2 µg/kg). As previously reported, one subject with metastatic breast cancer in cohort 2 (1 µg/kg) remained on treatment for 10 cycles with stable disease; although she had unmeasurable disease by RECIST criteria, she had three sub-centimeter hepatic lesions that disappeared at the end of cycle 8 before she discontinued for clinical progression/symptomatic deterioration at cycle 10. This subject had received three prior HER2 targeting regimens which initially included pertuzumab plus trastuzumab followed by trastuzumab and TDM1 as monotherapies. Dose escalation continues and no dose limiting toxicities have been observed to date at 6.75 µg/kg (Cohort 6).

The HER2+ breast cancer expansion cohort is planned to be initiated in 2Q21 at a dose of 10 μg/kg (anticipated to be a therapeutic dose level), pending adequate safety from the 10 μg/kg dose escalation cohort. Dose escalation in all HER2+ tumor types will continue (including potential cohorts beyond 10 µg/kg) to determine the recommended Phase 2 dose while the breast cancer expansion cohort collects efficacy and safety data. As doses higher than 10 μg/kg are considered to be tolerable in the dose escalation cohort, the dose will be increased in the breast cancer cohort accordingly.

Title: Preclinical Characterization of a Novel CTLA-4-Targeted ETB for Direct Treg Depletion
Authors: Khanna, Caleigh Howard, Lilia A. Rabia, Alvaro Aldana, Jay Zhao, Asis Sarkar, Eric Williams, Banmeet Anand, Betty Chang, Chris Moore, Hilario J. Ramos, Aimee Iberg — Molecular Templates Inc., Austin, TX.
Abstract # 1627
Current CTLA-4 antibodies have shown efficacy in oncology but have been limited by toxicity issues and an inability to clear regulatory T cells (Tregs) from the tumor microenvironment (TME). CTLA-4-targeted ETBs are designed to preferentially deplete Tregs in the TME to improve efficacy and reduce the toxicity associated with CTLA-4 targeted antibodies. This study explored the preclinical characterization of a lead candidate CTLA-4-targeted ETB. CTLA-4-ETB-A directly binds and specifically kills CTLA-4 positive cells in vitro and induces apoptosis of ex-vivo expanded Tregs. CTLA-4-ETB-A is designed to bind CTLA-4 in a manner unique from classic blocking antibodies and is not expected to have sustained blocking ability in vivo due to the relatively short half-life of an ETB compared to a neutralizing monoclonal antibody. The authors predict this will allow for focused Treg depletion in the TME based on target expression levels, while sparing autoreactive T cell activation in the periphery to reduce or eliminate the toxicity seen with CTLA-4 antibodies. In a transgenic mouse model expressing human CTLA-4 and bearing syngeneic subcutaneous tumors, CTLA-4 expression was highest on the Treg cells within the tumor microenvironment compared to other T cell populations and compartments. In this model, it was demonstrated that ETB treatment depletes Tregs in the TME, supporting the overall hypothesis. Peripheral CD4+ T cell proliferation was observed in response to ETB treatment. Initial tox assessment was performed in a non-human primate (NHP) model. ETB candidate A was well tolerated up to 450 μg/kg. An increase in proliferating CD4+ and CD8+ central memory T cells was observed and is a potential pharmacodynamic effect.

Title: Engineered Toxin Bodies Targeting PD-L1 to Alter Tumor Immunophenotypes and Delivery Broad Antigenic Diversity and Patient Coverage
Authors: Swati Khanna, Elizabeth Saputra, Wenzhao Dong, Lindsey Aschenbach, Lilia A. Rabia, Garrett L. Cornelison, Michaela Sousares, Jay Zhao, Lee Robinson, Betty Chang, Hilario J. Ramos, Joseph D. Dekker
Molecular Templates Inc., Austin, TX
Abstract # 1628
MT-6402 is an ETB designed to deliver a unique and dual mechanisms of action approach for directly targeting tumors that express PD-L1 on the tumor and/or the TME. Unlike current checkpoint inhibitors which only bind PD-L1 and sterically block interactions with PD-1, MT-6402 directly destroys PD-L1+ tumor and TME immune cells. MT-6402 has dual mechanisms of action that include the enzymatic destruction of ribosomes and the delivery of a viral class I antigen derived from CMV (pp65) into the targeted tumor, referred to as Antigen Seeding Technology (AST), for presentation on the target tumor cell surface to alter the tumor immunophenotype and induce a CMV specific T-cell response. MT-6402’s antigen seeding CMV pp65 payload covers the largest MHC haplotype in the US. Delivery of foreign antigens that are restricted to additional MHC haplotypes could broaden the patient population that could benefit from AST. ETBs based on MT-6402 that deliver additional antigens retain expected potency and target binding, while also activating donor CTLs with matched haplotypes. ETBs delivering antigens to a broader population are under investigation for in vivo safety, efficacy and function. The MT-6402 IND filing has been accepted by the FDA with the Phase 1 first-in-human study expected to begin dosing in 2Q21.

On April 12, 2021 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported the preclinical results of five of the company’s novel drug candidates at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Ascentage Pharma, APR 12, 2021, View Source [SID1234577936]). These studies are from seven preclinical studies in various tumor types and have signified the therapeutic potential of multiple combination therapies in cancer.

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The AACR (Free AACR Whitepaper) annual meeting is one of the world’s largest and long-standing scientific gatherings in the field of cancer research. Covering some of the most cutting-edge advances in all the areas of oncology research and innovation, the annual event attracts tremendous interest from the global cancer research community.

Results from the seven preclinical studies selected for poster presentations at this year’s AACR (Free AACR Whitepaper) annual meeting include:

Candidate

Title

Abstract#

HQP1351

FMS-like tyrosine kinase 3 (FLT3) inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 in preclinical models of FLT3-mutant acute myeloid leukemia (AML)

1096

ATP-site inhibitor olverembatinib, HQP1351, enhanced the effect of allosteric inhibitor on the resistance conferred by the compound mutations of BCR-ABL

1463

APG-2575

BCL-2 inhibitor APG-2575 and homoharringtonine (HHT) synergistically induces apoptosis and inhibits tumor growth in preclinical models of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS)

981

Inhibition of BCL-2 (by APG-2575) and CDK4/6 synergistically induces cell cycle arrest and apoptosis in ER⁺ breast cancer

976

APG-1387

Therapeutic potential of inhibitor of apoptosis protein (IAP) inhibitor APG-1387 combined with DR5 agonist monoclonal antibody (mAb) CTB-006 in preclinical models of solid tumors

1924

APG-1252

Targeting BCL-xL addiction with APG-1252 (pelcitoclax) to overcome apoptotic blockade in neuroendocrine neoplasm (NEN)

984

APG-2449

Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation

968

"These results presented at this year’s AACR (Free AACR Whitepaper) Annual Meeting are a testament to our continuous effort to address existing unmet medical needs, and provide strong scientific rationale for further investigations of our core drug candidates in combinations with therapies of other mechanism of actions and targeted pathways," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Combination therapy is playing an increasingly important role in cancer treatment. We will strive to make more progress of our core drug candidates and to hopefully bring these potential therapeutics to patients as early as possible."

FMS-like tyrosine kinase 3 (FLT3) inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 in preclinical models of FLT3-mutant acute myeloid leukemia (AML)

Abstract/Poster Number: 1096
Background
AML accounts for 80% of acute leukemias in adults. FLT3 gene mutations are observed in approximately 30% of patients with AML and augur a poor prognosis. Despite antitumor effects of selective FLT3 inhibitors, resistance to these agents continues to pose a formidable clinical challenge. The expression of pro-survival protein BCL-2 is frequently dysregulated, conferring resistance to FLT3 inhibitors, in AML. In this study, we explored the combination of clinical stage multikinase inhibitor HQP1351 (which also targets FLT3) and BCL-2-selective inhibitor APG-2575 in preclinical models of FLT3-mutant AML.

Conclusion
Taken together, our data suggest that FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-mutant AML. The results provide scientific rationale for clinical development of HQP1351 combined with APG-2575 in patients with FLT3-ITD-mutant AML.

ATP-site inhibitor olverembatinib, HQP1351, enhanced the effect of allosteric inhibitor on the resistance conferred by the compound mutations of BCR-ABL

Abstract/Poster Number: 1463
Background
Treatment with tyrosine kinase inhibitors (TKIs) directed against the ATP-binding site of BCR-ABL promotes recovery of Ph+ leukemia. However, emergence of gatekeeper mutation T315I and compound mutants confer resistance to these TKIs. The allosteric inhibitor, asciminib, effectively inhibits BCR-ABL kinase through binding to the myristoyl-binding site. Combining asciminib with ponatinib can overcome only a subset of the resistance caused by BCR-ABL compound mutants. Olverembatinib (HQP1351) is a new generation TKI targeting BCR-ABL and currently in development for r/r CML. The purpose of this study is to evaluate whether a novel combination of olverembatinib and asciminib, targeting both ATP pocket and allosteric region of BCR-ABL protein, can promote the inhibitory effect on the kinase harboring compound mutations.

Conclusion
Our results demonstrated that the combination of ATP binding site inhibitor olverembatinib and allosteric inhibitor have synergistic anti-tumor effect on tumor cells harboring single or compound mutations in BCR-ABL. This novel strategy may help to overcome the secondary compound mutations post the treatment with TKIs.

BCL-2 inhibitor APG-2575 and homoharringtonine (HHT) synergistically induces apoptosis and inhibits tumor growth in preclinical models of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS)

Abstract/Poster Number: 981
Background
The AML treatment landscape has improved dramatically in the past decade, with improved objective response rates and overall survival after treatment with newly approved targeted therapies. BCL-2 inhibition combined with a hypomethylating agent or low-dose cytosine arabinoside (Ara-C) is also effective in previously untreated elderly patients who are not candidates for standard induction therapy. However, the effect of BCL-2 inhibition is commonly weakened when tumor cells upregulate antiapoptotic protein MCL-1 to escape apoptosis. Thus, combination therapy is introduced to suppress MCL-1 levels. HHT (omacetaxine mepesuccinate) has been widely used in Chinese patients with AML for 30 years. As an inhibitor of protein synthesis, HHT decreases MCL-1. This study investigated the effect of combining clinical stage BCL-2 selective inhibitor APG-2575 with HHT in AML and MDS cells, as well as murine xenograft tumor models.

Conclusion
In summary, APG-2575 synergizes with HHT to potentiate antitumor activity in preclinical models of AML/MDS. HHT suppresses MCL-1 protein, preventing or abolishing formation of MCL-1:BIM, MCL-1:PUMA, and MCL-1:BAK complexes, and hence allowing prodeath proteins to fully engage in tumor cell apoptosis induction. Our results provide scientific rationale for clinical development of APG-2575 plus HHT in patients with AML/MDS.

Inhibition of BCL-2 (by APG-2575) and CDK4/6 synergistically induces cell cycle arrest and apoptosis in ER⁺ breast cancer

Abstract/Poster Number: 976
Background
Estrogen receptor positive (ER⁺)/human epidermal growth factor receptor 2 negative (HER2-) tumors represent the most common subset (about 75%) of all breast cancer cases. Combination treatment with endocrine therapy and a CDK4/6 inhibitor (CDK4/6i) is now the standard of care in early metastatic ER+ breast cancer. However, relapse or resistance to such combination therapy nearly inevitably occurs. Antiapoptotic protein BCL-2 is overexpressed in most cases of primary and metastatic ER+ breast cancer. We have shown that clinical-stage BCL-2 selective inhibitor APG-2575 enhances antitumor activity when combined with palbociclib in ER⁺ breast cancer xenograft models, including malignancies that are resistant to tamoxifen or progress after CDK4/6i treatment. We investigated mechanisms of action (MOAs) for synergistic effects of this combination.

Conclusion
Taken together, palbociclib drives breast cancer cells into a senescent state, and APG-2575 potentiates this antitumor effect by inducing cellular apoptosis. When combined with APG-2575, palbociclib inhibits MCL-1 expression and MCL-1:BIM complex formation as results of BCL-2 inhibition. Therefore, palbociclib reduces the threshold for apoptosis, while APG-2575 induces apoptosis by disrupting BCL-2:BIM complexes as well as enhancing expression of BIM and Noxa. Similar to palbociclib, APG-2575 also causes cell cycle arrest, and both agents collaboratively induce apoptosis in the combination setting. Our data reveal a viable MOA for synergistic effects, strengthening the scientific rationale for clinical development of the combination of the BCL-2 selective inhibitor APG-2575 and CDK4/6i palbociclib-based therapy in patients with ER+/HER2− breast cancer.

Therapeutic potential of inhibitor of apoptosis protein (IAP) inhibitor APG-1387 combined with DR5 agonist monoclonal antibody (mAb) CTB-006 in preclinical models of solid tumors

Abstract/Poster Number: 1924
Background
TNF-related apoptosis-inducing ligand (TRAIL) receptor (DR4 or DR5) agonists are promising agents for cancer therapy because they induce apoptosis selectively in cancer cells. However, their clinical effect is hampered by either primary or acquired resistance in cancer cells. Second mitochondria-derived activator of caspase (Smac) mimetics that antagonize the IAPs potently sensitize cancer cells to TRAIL-induced apoptosis in a caspase-8-dependent manner. We evaluated antitumor effects of small-molecule IAP antagonist APG-1387combined with an agonist mouse mAb directed against TRAIL death receptor type 5 (DR5) termed CTB-006 in the preclinical setting. Both agents are in phase I/II clinical development for patients with solid tumors.

Conclusion
In summary, our results suggest great potential of combination therapy with APG-1387 and CTB-006 for solid tumor therapy and deserves further clinical investigation.

Targeting BCL-xL addiction with APG-1252 (pelcitoclax) to overcome apoptotic blockade in neuroendocrine neoplasm (NEN)

Abstract/Poster Number: 984
Background
Current targeted therapies such as VEGFR inhibitor sunitinib and mTOR inhibitor everolimus extend progression-free survival (PFS) in patients with Grade 1 (G1) and G2 neuroendocrine tumors (NET), but the objective response rate remains low. The median PFS in patients with advanced neuroendocrine carcinoma (NEC) receiving platinum-based therapy is only 3 to 4 months. Hence, more effective therapy is needed to improve clinical outcomes. This study explored if BCL-2 family antideath proteins play a role in NEN tumorigenesis and whether clinical-stage dual BCL-2/BCL-xL inhibitor APG-1252 might overcome intrinsic apoptotic blockade in NEN.

Conclusion
In summary, the results suggest that BCL-xL plays an important role in NEN. Cellular sensitivity to BCL-2/BCL-xL inhibitor APG-1252-M1 correlates with baseline BCL-xL complex levels. In NEN patient samples, MCL-1 was also highly expressed, implicating its potential negative regulatory effect on sensitivity to APG-1252. Concurrent expression of BCL-xL and MCL-1 proteins suggests that a combination treatment targeting both proteins might be more effective in NEN. Our findings inform development of a BCL-2/BCL-xL inhibitor for NEN therapy.

Focal adhesion kinase (FAK) inhibitor APG-2449 sensitizes ovarian tumors to chemotherapy via CD44 downregulation

Abstract/Poster Number: 968
Background
Ovarian cancer is one of the deadliest malignancies in women, and up to 70% of patients with epithelial ovarian cancer have FAK overexpression, amplification, or activation. FAK plays an important role in cellular migration, growth factor signaling, cell cycle progression, cellular survival and chemoresistance. This biomarker is also significantly associated with higher tumor stage, metastasis, and shorter overall survival in patients with ovarian cancer. Inhibition of FAK is therefore emerging as a promising treatment target. APG-2449 is a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor. In this study we investigated antitumor activity of APG-2449 combined with standard-of-care chemotherapeutics in ovarian cancer in the preclinical setting.

Conclusion
In summary, our data suggest that FAK inhibition by APG-2449 sensitizes ovarian tumors to chemotherapeutics in preclinical tumor models of ovarian cancer. The synergistic antitumor activity was mediated by downregulation of CD44⁺ or ALDH1⁺ cancer stem cell populations. These findings encourage clinical development of APG-2449 in combination with chemotherapies for treatment of ovarian cancer.