On April 12, 2021 Schrödinger (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that new preclinical data from its CDC7 inhibitor program in a poster session on April 10, 2021, during the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Virtual Meeting (Press release, Schrodinger, APR 12, 2021, View Source [SID1234577928]). The data showed that Schrödinger’s picomolar CDC7 inhibitors were highly selective and inhibited tumor cell growth alone and in combination with several approved and investigational cancer treatments.

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CDC7 is a protein kinase that is required for DNA replication initiation and is involved in DNA replication stress response. CDC7 is thought to be linked to cancer cells’ proliferative capacity and ability to bypass normal DNA damage responses. Targeting proteins that play important roles in DNA replication and replication stress is gaining momentum as a new therapeutic approach based on the proliferative capacity of cancer cells to bypass DNA damage responses.

"Based on our preclinical data, we believe we have identified the most potent CDC7 inhibitors reported to date, capable of inhibiting cell growth and causing programmed cell death in both blood and solid tumors, while sparing healthy cells," said Karen Akinsanya, Ph.D, executive vice president, chief biomedical scientist and head of discovery R&D at Schrödinger. "We’re excited by the rapid progress in our internal pipeline. We look forward to selecting development candidates and moving multiple oncology programs into IND-enabling studies this year."

Additional Details About the Data Presented at AACR (Free AACR Whitepaper)

The presentation, "Discovery of novel CDC7 inhibitors that disrupt cell cycle dynamics and show anti-proliferative effects in cancer cells," highlighted preclinical data with multiple lead molecules discovered by Schrödinger scientists. The company’s CDC7 inhibitor compounds demonstrated dose-dependent picomolar potency as measured by in vitro inhibition of CDC7 enzymatic activity. The compounds were highly selective, inducing apoptosis in cancer cells but not in normal fibroblasts. They also showed synergy with several approved and investigational cancer therapies that modulate apoptosis, DNA repair mechanisms and DNA checkpoints, including venetoclax, olaparib, ceralasertib and adavosertib. Additionally, Schrödinger’s compounds significantly inhibited tumor growth in mouse models of both acute myeloid leukemia and colorectal cancer. Taken together, these data provide further rationale for developing CDC7 inhibitors as a potential therapeutic approach, particularly in combination with existing therapies.

Schrödinger’s MALT1 and Wee1 Programs

Schrödinger is continuing to advance its MALT1 and Wee1 inhibitor programs. Targeting MALT1 is emerging as a potential therapeutic strategy to treat certain relapsed or resistant B-cell lymphomas and chronic lymphocytic leukemia. In December 2020, Schrödinger scientists presented preclinical data at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting highlighting that its MALT1 inhibitors demonstrated anti-tumor activity alone and in combination with approved anti-cancer therapies in models of B-cell lymphoma.

Similar to CDC7, Wee1 targets cancer through replication stress and DNA repair mechanisms. The company has identified highly selective, potent Wee1 inhibitors with optimized drug-like properties, including no observable inactivation of CYP3A4, a key liver enzyme. Lead compounds exhibited favorable pharmacokinetic properties and strong anti-tumor activity in preclinical models.

Based on the strong data generated to date, Schrödinger is on track to move forward with IND-enabling studies for its MALT1, CDC7 and Wee1 programs. Subject to completion of the preclinical data packages, the company expects to submit up to three IND applications in 2022, with the first submission expected in the first half of next year.

Webcast Information

Today at 10:00 a.m. ET, Schrödinger will host a webcast to review the preclinical data presented from its CDC7 program at the virtual AACR (Free AACR Whitepaper) Annual Meeting. The company will also provide an overview of two other internal programs, MALT1 and Wee1, as well as highlight the role of its computational platform in accelerating the discovery of its novel molecules. The webcast will be available under "News & Events" in the investors section of Schrödinger’s website, View Source and will be archived for approximately 7 days.

On April 12, 2021 Cardiff Oncology, Inc. (the "Company") Presented its corporate slide presentation (Presentation, Cardiff Oncology, APR 12, 2021, View Source [SID1234577946]).

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On April 12, 2021 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the presentation of three posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting being held virtually from April 10-15, 2021 .

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"These data highlight the significant potential of our advanced and differentiated ROR1 platform, where cirmtuzumab has demonstrated promising preclinical and clinical activity across a broad spectrum of cancer indications. The results from the current preclinical studies create additional optionality to pursue future indications, which we are actively evaluating while we advance our Phase 2 cirmtuzumab program in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) and advance our earlier-stage CAR-T and CAR-NK cell programs that also target ROR1," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO.

Poster Presentations:

Session Date and Time: April 10, 2021 8:30 AM – 11:59 PM ET
Session Title: Stem Cell Biology
Poster Title: A Phase 1b Trial of Cirmtuzumab and Paclitaxel in Locally Advanced/Unresectable or Metastatic Her2 Negative Breast Cancer (Poster #LB255)
- In this Phase 1b investigator-initiated clinical trial from the University of California San Diego (UC San Diego) School of Medicine, 15 patients were treated with cirmtuzumab and paclitaxel after receiving a median of six prior therapies for metastatic disease. Of 15 intent-to-treat patients as of April 10, 2021, eight patients (53%) had a best response of partial response (PR), one of which remained durable for 52 weeks, and four patients (27%) had stable disease (SD). Of the 14 patients who were evaluable for efficacy per protocol, eight patients (57%) had a PR and four patients (29%) had SD. All reported adverse events were related to paclitaxel except for one Grade 3 neutropenia that was categorized as possibly related to cirmtuzumab. No patient stopped cirmtuzumab due to toxicity, no dose reductions of cirmtuzumab were required and no dose limiting toxicities were observed. The authors concluded that as of the cutoff date, cirmtuzumab given with paclitaxel was well-tolerated and demonstrated no added toxicity over what was expected with paclitaxel alone in heavily pre-treated patients with metastatic breast cancer. As of the cutoff date, all pre-treatment breast cancer samples available for analysis expressed ROR1 as assessed by immunohistochemistry. The authors concluded that further clinical evaluation of cirmtuzumab was warranted in patients with breast cancer.
Poster Title: Inhibition of ovarian and endometrial cancer cell proliferation by an anti-ROR1 monoclonal antibody (Poster #1062)
Session Title: Combination Therapies
Session Date and Time: April 10, 2021 8:30 AM – 11:59 PM ET
In this preclinical study from the University of New South Wales, high-grade serous ovarian cancer (HGSOC) and endometrial cancer cell lines were treated with cirmtuzumab alone or in combination with chemotherapeutic agents, cisplatin, paclitaxel, or the PARP inhibitor olaparib. The authors concluded that cirmtuzumab demonstrated single agent activity against these tumor types, and also enhanced the anti-proliferative effects of commonly-used chemotherapies in these cancers. Future studies will further evaluate cirmtuzumab in ovarian and endometrial cancers in vitro and in relevant in vivo models.
Poster Title: Selective androgen receptor degraders for the treatment of androgen receptor-positive, triple-negative breast cancer (Poster # 1235)
Session Title: Novel Antitumor Agents
Session Date and Time: April 10, 2021 8:30 AM – 11:59 PM ET
In this preclinical study from the University of Tennessee, androgen receptor (AR)-positive triple negative breast cancer (TNBC) cell proliferation and tumor growth were inhibited using Oncternal’s investigational selective androgen receptor degraders (SARDs). Notably, the SARDs demonstrated anti-tumor activity in a TNBC patient-derived xenograft model expressing a splice variant of the AR. Oncternal believes that these results support further development of Oncternal’s SARDs as a potential treatment for women affected by the luminal androgen receptor (LAR) subtype of TNBC.
About Cirmtuzumab
Cirmtuzumab is an investigational, potentially first-in-class monoclonal antibody targeting ROR1, or Receptor tyrosine kinase-like Orphan Receptor 1. Cirmtuzumab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of MCL or CLL, in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine: (i) a Phase 1b clinical trial of cirmtuzumab in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, and (ii) a Phase 2 clinical trial of cirmtuzumab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen – not usually expressed on adult cells, and its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically targeting ROR1 expressing tumors. This led to the development of cirmtuzumab, that binds this critical epitope of ROR1, which is highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when cirmtuzumab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to cirmtuzumab for the treatment of MCL and CLL/small lymphocytic lymphoma. Cirmtuzumab is in clinical development and has not been approved by the FDA for any indication.

About SARDs
Oncternal’s preclinical Selective Androgen Receptor Degrader (SARD) program is based on inventions by Professors Duane Miller and Ramesh Narayanan from the University of Tennessee Health Science Center (UTHSC) in Memphis, TN. The androgen receptor (AR) is a validated target for the treatment of castration-resistant prostate cancer (CRPC) and there are currently several FDA-approved AR-targeting therapies. However, resistance development occurs, often through mutations or AR splice variants rendering most therapies ineffective. In preclinical studies, Oncternal’s investigational SARDs have demonstrated activity against prostate cancer tumors resistant to approved AR-targeting therapies. Oncternal is currently evaluating strategic development options for SARDs as potential therapies for castration-resistant prostate cancer (CRPC) and LAR-TNBC as well as AR-driven non-oncology indications.

On April 12, 2021 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune/inflammatory diseases, reported the presentation of two posters on the company’s clinical and preclinical oncology programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Alpine Immune Sciences, APR 12, 2021, View Source [SID1234577912]).

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CT213: NEON-1: A First-in-Human Phase I Open-Label Study of ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, in Advanced Malignancies

Dr. Mark Voskoboynik from Nucleus Network and The Alfred Hospital in Melbourne, Australia, presented a Trials in Progress poster describing the ongoing first-in-human, phase 1 clinical trial involving monotherapy with ALPN-202, the company’s lead oncology program.
The trial, NEON-1, includes separate parts for dose escalation and expansion cohorts, and is enrolling patients with advanced solid tumors or lymphoma. Dose escalation continues to progress, with no dose-limiting toxicities to date.
P1740: Engineered Variant Domain Fusion Proteins Provide Checkpoint Inhibition and Tumor Antigen Dependent CD28 Costimulation Resulting in Potent Anti-Tumor Immunity

Alpine researchers demonstrated the use of directed evolution to engineer novel variant immunoglobulin domain (vIgD) Fc fusion proteins that enable tumor antigen-dependent CD28 costimulation.
The fusion proteins targeted the PD-L1 or HHLA2 tumor antigens, and demonstrated potent efficacy in antigen-positive tumor models in vitro and in vivo.
"Together, these presentations summarize the potential for an exciting, emerging CD28 costimulation portfolio," said Stanford Peng, MD, PhD, Alpine’s President and Head of Research and Development. "We look forward to the opportunity to present initial clinical data from NEON-1 at an upcoming scientific meeting and are optimistic about the potential to advance one or more of our preclinical programs toward the clinic in the near future."

Full abstracts are available on the AACR (Free AACR Whitepaper) Virtual Annual Meeting website and posters for both presentations are available on the Scientific Publications page of Alpine’s website.

About Alpine’s Directed Evolution Platform

Alpine’s directed evolution platform engineers native immune proteins, primarily of the immunoglobulin or tumor necrosis factor (receptor) superfamilies, into novel functional domains: variant immunoglobulin domains (vIgDs) and/or variant TNF domains (vTDs), respectively. These domains have acquired unique functional properties designed to benefit patients with cancer or inflammatory diseases.

About ALPN-202

ALPN-202 is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor with the potential to improve upon the efficacy of combined checkpoint inhibition while limiting significant toxicities. Preclinical studies of ALPN-202 have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. NEON-1 (NCT04186637), a Phase 1 study of ALPN-202 in patients with advanced malignancies, is currently enrolling. Alpine is also targeting the initiation of NEON-2, a Phase 1 combination study of ALPN-202 and a PD-1 inhibitor, later this year.

On April 12, 2021 InterVenn Biosciences, the leader in glycoproteomics, reported that it has developed a glycoproteomics-based signature that accurately predicts which malignant melanoma patients will respond to checkpoint inhibitor therapy (Press release, InterVenn Biosciences, APR 12, 2021, View Source [SID1234577929]). InterVenn’s assay, performed via blood-based liquid biopsy as opposed to a tumor tissue sample, demonstrated that patients who test positive for the InterVenn signature have a 9-fold higher likelihood of responding to checkpoint inhibitors compared to those who test negative. In a longitudinal study of 36 patients, all of whom received checkpoint-inhibitor therapy, 70 percent of patients who tested positive for the signature remained progression-free at 18 months after treatment initiation, as compared to patients who tested negative, 50 percent of whom showed progression as early as at 1 month. The results were presented in a poster presentation (#387) at the virtual AACR (Free AACR Whitepaper) Annual Meeting 2021: Discovery Science Driving Clinical Breakthroughs.

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Checkpoint inhibitors have proven to be powerful anti-tumor drugs, oftentimes providing long-lasting durable responses and cancer remissions in many indications. However, only approximately 1 in 3 patients will respond, exposing those not deriving any benefit needlessly to potentially serious adverse events. Efforts at finding biomarkers to predict treatment response and guide therapy using DNA-or RNA-based tests have so far had only marginal success. In contrast, InterVenn’s glycoproteomic signature was shown highly effective in identifying patients who will benefit from this therapy, thus potentially avoiding the risk of serious side effects in patients who are unlikely to benefit from these drugs. Further studies are ongoing.

The response-prediction signature was identified using InterVenn’s proprietary, patented foundational technology that leverages artificial intelligence and machine learning for ultra-high-throughput processing of mass spectrometry data to identify and apply glycopeptides as biomarkers for diagnosis and treatment selection. These findings are the latest in a series of developments from InterVenn in advancing the world’s first glycoproteomics-based LDT (Laboratory-Developed Test.) The company’s first diagnostic product, a non-invasive liquid biopsy test for ovarian cancer, will have final data from its initial clinical trial, V.O.C.A.L., in the first half of 2021. InterVenn’s on-site laboratory received CLIA certification in late 2020 to make its tests available to the medical community.

"We are getting closer to realizing the true potential of personalized medicine and to selecting the optimal therapy for each individual patient based on a deep understanding of the biology of their disease," said Klaus Lindpaintner, MD, Chief Scientific and Medical Officer of InterVenn. "By leveraging the power of AI, we have been able to make huge strides in generating and delivering valuable information to physicians to help them guide the care of their patients in ways which, without our powerful platform, have never before been possible."

To find out more about InterVenn Biosciences and how the company is leveraging artificial intelligence and mass spectrometry to the transformation of medical technology, visit View Source For all media inquiries about InterVenn Biosciences, please contact Andrea Vuturo at [email protected]