1stOncology™: Cancer Intelligence Service – Page 14342 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Aptose Presents Preclinical Data on APTO-253 at 2018 AACR Annual Meeting

On April 17, 2018 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data exploring the mechanism of action of APTO-253, the company’s clinical stage product candidate (Press release, Aptose Biosciences, APR 17, 2018, View Source;p=RssLanding&cat=news&id=2343016 [SID1234525432]). The data, demonstrating heightened sensitivity of BRCA1 or BRCA2 mutated cancer cells to APTO-253, were presented in a poster Tuesday, April 17 at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held April 14-18, in Chicago, IL.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

The poster, entitled APTO-253 is a new addition to the repertoire of drugs that can exploit DNA BRCA1/2 deficiency, explored the mechanism of action of APTO-253, a small molecule with anti-proliferative activity against cell lines derived from a wide range of human malignancies. This study investigated the mechanism of action of APTO-253 to identify synthetic lethal interactions that can guide combination drug studies.

The research team found that APTO-253 stabilizes certain quadruplex DNA structures, causes DNA damage, and exhibits synthetic lethality comparable to olaparib – an FDA-approved targeted therapy that acts against cancers in people with hereditary BRCA1 or BRCA1 mutations, including some ovarian, breast and prostate cancers – albeit through a different mechanism. Unlike other drugs for which loss of this DNA repair function results in hypersensitivity, APTO-253 does not produce myelosuppression even at the maximum tolerated dose. The observations reported also identify γH2AX as a potential biomarker of clinical effect and open the window to more detailed studies of how APTO-253 promotes DNA damage and how it might be used clinically to treat patients with tumors harboring deficiencies in DNA repair.

The presentation will be published in the AACR (Free AACR Whitepaper) Conference Proceedings. The poster can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.
"We have clarified the mechanism of APTO-253 during the past year or so, including its mechanism to inhibit expression of the MYC gene, an oncogene that promotes tumor growth and resistance to drugs in AML and other cancers," said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer. "AML remains our primary focus for APTO-253, and we hope to re-initiate dosing of AML patients with APTO-253 in an open phase Ib trial during the 2nd quarter of 2018. In the current presentation at AACR (Free AACR Whitepaper), we report that cancer cells deficient in the BRCA1/2 DNA repair functions are hyper-sensitive to APTO-253, analogous to the FDA-approved PARP inhibitor olaparib, but acting through a different mechanism. The findings reveal potential new solid tumor indications for APTO-253. Importantly, APTO-253 does not produce myelosuppression even at the maximum tolerated dose, which significantly distinguishes it from other cancer chemotherapies."

About APTO-253
APTO-253 is a clinical-stage small molecule targeted therapeutic agent that inhibits expression of the c-Myc oncogene, leading to cell cycle arrest and programmed cell death (apoptosis) in human-derived solid tumor and hematologic cancer cells, without causing general myelosuppression of the healthy bone marrow. The c-Myc oncogene is overexpressed in hematologic cancers, including acute myeloid leukemia (AML). Aptose researchers have reported the ability of APTO-253 to induce cell death, or apoptosis, in multiple blood cancer cell lines including AML, as well as in vitro synergy with various classes of conventional approved and investigational therapies for AML or myelodysplastic syndromes (MDS). New findings reveal that APTO-253 might also serve certain solid tumor patients with BRCA1/2 mutations, but without causing toxicity to the normal bone marrow functions.

Apexian Pharmaceuticals to present two poster sessions at AACR meeting in Chicago – April 14-18, 2018

On April 17, 2018 Apexian Pharmaceuticals, a clinical-stage biotechnology company focused on developing safe and effective therapy for patients with high unmet medical needs, reported that it will present two key poster sessions at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Meeting, which will be held at McCormick Place in Chicago, Illinois from April 14 – 18, 2018 (Press release, Apexian Pharmaceuticals, APR 17, 2018, View Source [SID1234525431]). Dr. Mark Kelley, Apexian’s Chief Scientific Officer, along with the research team will available at the posters session. The company will present two posters on combination therapy of APX3330 in pancreatic cancer and APE1 signaling pathway.

The titles and locations for these sessions are:
"Combination Therapy in PDAC Involving Blockade of the APE1/Ref-1 Signaling Pathway: An Investigation into Drug Synthetic Lethality and Anti-Neuropathy Therapeutic Approach"
Session Date and Time: Tuesday, April 17, 2018 from 1:00 – 5:00 PM
Location: McCormick Place South, Exhibit Hall A, Poster Section 37
"APE1/Ref-1 Redox Signaling Regulates HIF1a-mediated CA9 Expression in Hypoxic Pancreatic Cancer Cells: Combination Treatment in Patient-derived Pancreatic Tumor Models"
Session Date and Time: Monday, April 16, 2018 from 1:00 – 5:00 PM
Location: McCormick Place South, Exhibit Hall A, Poster Section 41
The poster sessions will add significant new information gathered on the effectiveness of Apexian’s lead clinical candidate, APX3330, and the ongoing research on the APE1/Ref-1 target.

Preclinical Data Highlighting ADXS-Hot as Immunotherapy with Potential to Target Hotspot Cancer Mutations across Multiple Cancer Types Presented in Poster Discussion at The AACR Annual Meeting

On April 17, 2018 Advaxis, Inc. (NASDAQ: ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported the presentation of ADXS-HOT preclinical data in a poster discussion entitled "Targeting Shared Hotspot Cancer Mutations with a Listeria monocytogenes Immunotherapy Induce Potent Anti-Tumor Immunity" at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting underway in Chicago (Press release, Advaxis, APR 17, 2018, View Source [SID1234525430]). The discussion, held yesterday, was led by Daniel O. Villarreal, Ph.D., Principal Scientist at Advaxis. The ADXS-HOT franchise leverages the Company’s proprietary Lm Technology to target common mutations in tumor driver genes.

This study’s objective was to identify and target common (public or shared) mutations (hotspots) and to determine if the ADXS-HOT platform could effectively target those hotspots and control tumor growth. Results indicate that ADXS-HOT could achieve this in preclinical models against single and multi-target constructs. The full abstract is available here: View Source
"The results of this preclinical work with ADXS-HOT represent an exciting opportunity that may allow us to develop disease-specific immunotherapies that have the potential to be effective against multiple targets, capable of generating high-avidity T cells against shared of public mutations, as well as multiple proprietary highly immunogenic cancer-testes and oncofetal antigens for multiple tumor types," said Robert G. Petit, Ph.D., Executive Vice President and Chief Scientific Officer of Advaxis. "Additionally, the results show increased functionality and resiliency in CD8 T cells upon restimulation, indicating the potential not only to increase the number and frequency of CD8 T cells, but to strengthen them."

About ADXS-HOT
ADXS-HOT leverages the Company’s proprietary Lm technology to target common "hotspot" mutations. ADXS-HOT products are designed to target acquired shared or "public" mutations in tumor driver genes along with cancer-testes and oncofetal tumor-associated antigens that are shared by multiple patients. Although ADXS-HOT has not been tested in patients, in theory, products would be designed to treat all patients with a particular type of cancer, without the need for pre-treatment testing, biopsy, DNA sequencing or diagnostic testing.

Aduro Biotech Highlights Preclinical Data for Three Programs Reported at the American Association for Cancer Research Annual Meeting

On April 17, 2018 Aduro Biotech, Inc. (NASDAQ:ADRO) reported that data from three of the company’s programs were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) this week (Press release, Aduro Biotech, APR 17, 2018, View Source;p=RssLanding&cat=news&id=2343034 [SID1234525429]). The poster presentations detailed:

Updated preclinical data for ADU-S100, a first-in-class small molecule therapeutic in Phase 1 studies targeting the STimulator of INterferon Genes (STING) pathway;
New preclinical data for ADU-1604, an anti-CTLA-4 antibody scheduled to enter clinical development in the second half of 2018; and,
Preclinical data for BION-1301, an anti-APRIL antibody currently in a Phase 1/2 study for the treatment of patients with multiple myeloma.

"These robust and new data continue to elucidate the diverse mechanisms by which our immunotherapies may provide new therapeutic alternatives for the large majority of patients that do not currently benefit from available cancer immunotherapies," said Andrea van Elsas, Ph.D., chief scientific officer of Aduro. "For ADU-S100, we’ve confirmed in preclinical models that signaling through the STING pathway is critical to elicit tumor-reactive CD8+ T cells, the cornerstone of effective, durable and systemic anti-tumor immunity as evident from rejection of distant tumors. Importantly, these preclinical data show that adding checkpoint inhibitors to an ADU-S100 treatment regimen can eradicate tumors unresponsive to anti-PD-1 immunotherapy."

Dr. van Elsas continued, "We also reported data on our anti-CTLA-4 antibody, ADU-1604, and expect to initiate clinical studies based on this data. In addition, our first-in-class antibody BION-1301 blocks APRIL from binding to both BCMA and TACI and may provide a differentiated approach to treating patients with multiple myeloma who do not benefit from or are resistant to current therapies. We look forward to confirming these data through our ongoing Phase 1/2 clinical study."
Presentation Title (Abstract #631): Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8+ T cell immunity that effectively combines with checkpoint inhibitors
On Sunday, April 15, 2018, Sarah McWhirter of Aduro Biotech presented updated preclinical data demonstrating that an optimized dosing regimen of ADU-S100 administered intratumorally activates acute innate immunity as well as adaptive CD8+ T cells necessary and sufficient for systemic and durable anti-tumor immunity. The data show that activation of the STING pathway by ADU-S100 mediates local induction of type I interferon and TNFα and subsequently CD8+ T cell induction to stimulate an immune response sufficient to reduce or eliminate both the injected and distal tumors.

In addition, combining ADU-S100 with checkpoint inhibitors enhances the durable immunity even in tumors that are resistant to anti-PD-1 treatment. Aduro and Novartis are evaluating ADU-S100 in ongoing Phase 1 clinical studies, both as monotherapy for cutaneously accessible tumors and in combination with PDR001, an anti-PD-1 compound in advanced metastatic solid tumors and lymphomas. Additional studies combining ADU-S100 and other checkpoint inhibitors are planned.

Presentation Title (Abstract #1702): Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evolution of local and anti-CTLA-4 application
On Monday, April 16, 2018, Maaike Hendriks of Aduro Biotech presented preclinical data demonstrating that ADU-1604 binds a unique epitope on human CTLA-4 and was well-tolerated, enhanced T cell activation and inhibited tumor growth. Based on these data, Aduro plans to initiate a Phase 1 study in patients with advanced melanoma in the second half of 2018.

Presentation Title (Abstract #3780): Preclinical pharmacokinetics, pharmacodynamics and safety of BION-1301, a first-in-class antibody targeting APRIL for the treatment of multiple myeloma

On Tuesday, April 17, 2018, John Dulos of Aduro Biotech presented preclinical pharmacokinetic and pharmacodynamic data initially announced at the American Society of Hematology (ASH) (Free ASH Whitepaper) demonstrating that BION-1301 was well-tolerated. In addition, the binding of BION-1301 to APRIL (A Proliferation Inducing Ligand), a ligand for the receptors BCMA and TACI, resulted in decreased IgA, IgG and IgM production in a dose-dependent fashion. Aduro is evaluating BION-1301 in an ongoing Phase 1/2 study in patients with multiple myeloma.

About STING Pathway Activator Platform
The Aduro-proprietary STING pathway activator product candidates, including ADU-S100 (MIW815), are synthetic small molecule immune modulators that are designed to target and activate human STING. STING is generally expressed at high levels in immune cells, including dendritic cells. Once activated, the STING receptor initiates a profound innate immune response through multiple pathways, inducing the expression of a broad profile of cytokines, including interferons and chemokines. This subsequently leads to the development of a systemic tumor antigen-specific T cell adaptive immune response.

Aduro’s lead molecule, ADU-S100/MIW815, is the first therapeutic in development specifically targeting STING. In collaboration with Novartis, it is being tested in a Phase 1 monotherapy clinical trial and in a Phase 1b combination study with PDR001, an anti-PD-1 compound. Both studies are enrolling patients with cutaneously accessible, advanced/metastatic solid tumors or lymphomas. The trials are evaluating the ability of ADU-S100 to activate the immune system and recruit specialized immune cells to attack the injected tumor, leading to a broad immune response that seeks out and kills non-injected distant metastases. Initial clinical data are expected in the second half 2018.

About ADU-1604
Cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) is a negative regulator of T cell responses and is an immune checkpoint. Blocking CTLA-4 using antibodies may produce an anti-tumor response by enhancing T cell activation and their cancer cell killing activity in the tumor. This therapeutic target has been clinically validated by others in advanced melanoma. Aduro is developing a proprietary humanized anti-CTLA-4 antibody called ADU-1604 that binds to a unique epitope and its potency has been demonstrated in vitro and in vivo. Based on preclinical studies, Aduro believes that ADU-1604 when combined with innate and adaptive immune cell stimulators such as STING agonists and cancer vaccines, can display an amplified anti-tumor effect against poorly immunogenic tumors. ADU-1604 is anticipated to enter clinical development in the second half of 2018.

About BION-1301
Aduro is currently evaluating BION-1301, its most advanced proprietary B-select monoclonal antibody, as a novel therapy for multiple myeloma. Despite new treatments recently approved in multiple myeloma, this disease remains incurable as patients relapse, or become resistant to, currently-available therapies. In preclinical studies, Aduro has established that A PRoliferation-Inducing Ligand (APRIL) plays a crucial part in the protective bone marrow tumor microenvironment. In these studies, APRIL, through the B cell maturation antigen (BCMA), was shown to be critically involved in the survival, proliferation and chemoresistance of multiple myeloma, and upregulates mechanisms of immunoresistance, including PD-L1 upregulation. BION-1301, a humanized antibody that blocks APRIL from binding to its receptors, has been shown in preclinical studies to halt tumor growth and overcome drug resistance. In addition, BION-1301 also demonstrated the ability to inhibit immune suppressive effects of regulatory T cells via TACI but not BCMA in multiple myeloma blood and bone marrow. BION-1301 is currently being evaluated in a Phase 1/2 clinical study.

Sierra Late-Breaking Data Demonstrating SRA737 Preclinical Activity with PARPi to be Presented at the AACR 2018 Annual Meeting

On April 17, 2018 Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported preclinical results in two posters, including late-breaking data being presented today, for its Checkpoint kinase 1 (Chk1) inhibitor SRA737, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago, Illinois (Press release, Sierra Oncology, APR 17, 2018, View Source [SID1234525426]).

"The data presented within these posters demonstrate that SRA737, as monotherapy and in combination with a poly ADP-ribose polymerase inhibitor (PARPi) such as niraparib, has anti-tumor activity across a broad range of settings. Anti-tumor activity was observed both in homologous recombination repair (HRR) proficient cancers which are poor candidates for PARPi alone, and in HRR deficient tumor cells that have acquired resistance to either PARPi and/or platinum agents," said Dr. Christian Hassig, Chief Scientific Officer of Sierra Oncology. "We also observed inhibition of tumor growth in aggressive CCNE1-driven high grade serous ovarian cancer (HGSOC) patient-derived xenografts. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. Analogous to PARPi, which first exhibited robust activity in patients harboring BRCA mutations, Chk1 inhibitors such as SRA737 may prove effective in defined genetic backgrounds of high replication stress, such as CCNE1 amplification."
The efficacy of SRA737 monotherapy is currently being investigated in an ongoing Phase 1/2 clinical trial (NCT02797964) in replication stress-driven cancer including a patient cohort with CCNE1 amplified HGSOC.
Sierra is also planning to investigate SRA737 in combination with niraparib in a multicenter Phase 1b/2 study in subjects with metastatic castration-resistant prostate cancer (mCRPC), anticipated to be initiated in the fourth quarter of 2018. Janssen Research & Development, LLC will supply TESARO’s ZEJULA (niraparib) for the trial, which is to be led by Professor Johann de Bono, Regius Professor of Cancer Research, Head of the Division of Clinical Studies and Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.
The two posters will be available on the company’s website at www.sierraoncology.com.
SRA737 AACR (Free AACR Whitepaper) 2018 Late-Breaker: The Novel Oral Chk1 Inhibitor, SRA737, Is Active in Both PARP Inhibitor Resistant and CCNE1 Amplified High Grade Serous Ovarian Cancers
Data being presented in this late-breaking poster is from research conducted in the laboratory of Dr. Fiona Simpkins, Assistant Professor of Obstetrics and Gynecology at The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Approximately 20% of HGSOCs harbor CCNE1 gene amplification. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. These tumors show intrinsic resistance to PARPi and frequently are, or become resistant to, platinum therapy, leaving patients without effective treatment options. In this research, Chk1 inhibition by SRA737 as monotherapy in CCNE1 amplified ovarian cancer models was shown to: a) increase levels of replication stress and DNA double strand breaks, b) in turn leading to excessive genomic instability, c) resulting in subsequent tumor cell death, tumor regression and a profound survival benefit.

A distinct subgroup comprising approximately 50% of HGSOC have defective HRR genes (e.g. BRCA1/2 mutation). HRR deficient HGSOC are initially sensitive to PARPi but drug resistance ultimately emerges, frequently involving genetic reversion of BRCA mutated genes and partial restoration of HRR. HRR deficiency may also elevate sensitivity to Chk1 inhibition, given the well-established role of Chk1 in HRR, as well as other aspects of the replication stress response. In this research, SRA737 demonstrated activity as a single agent, as well as in combination with PARPi, in acquired PARPi-resistant cells. Furthermore, SRA737 in combination with PARPi demonstrated preliminary evidence of synergistic tumor growth inhibition in a HGSOC patient-derived xenograft model.

SRA737 AACR (Free AACR Whitepaper) 2018 Poster: The Chk1 Inhibitor, SRA737, Synergizes with the PARP Inhibitor, Niraparib, to Kill Carcinoma Cells via Multiple Cell Death Pathways
Sierra presented a second poster at AACR (Free AACR Whitepaper) with data from research conducted in the laboratory of Dr. Paul Dent, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia. The results demonstrate that the combination of SRA737 and niraparib was effective in HRR proficient ovarian and breast tumor cell lines and that both autophagic cell death and apoptotic pathways contribute to SRA737/niraparib-induced tumor cell killing. PARPi monotherapy is known to be substantially less effective in treating patients with HRR proficient tumors, making the combination with SRA737 a novel and potentially more effective treatment option. Moreover, the involvement of multiple cell death mechanisms may decrease the potential for tumors to develop resistance to these agents.