On April 12, 2021 NuCana plc (NASDAQ: NCNA) reported the presentation of five posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually April 9 to 14, 2021 (Press release, Nucana BioPharmaceuticals, APR 12, 2021, View Source [SID1234577911]). Data from all three of NuCana’s ProTides in clinical development were presented. Summaries of the posters are described below.

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!

NUC-3373

NuCana presented two posters on NUC-3373, its ProTide transformation of the active anti-cancer metabolite of 5-fluorouracil (5-FU), a very widely used anti-cancer drug. NUC-3373 has been designed to overcome the main challenges associated with 5-FU and capecitabine, including cancer-resistance mechanisms, the generation of toxic metabolites and unfavorable pharmacokinetic profile.

Poster Title: NUC-3373, a targeted inhibitor of thymidylate synthase, in patients with advanced colorectal cancer

This poster describes further encouraging interim data from 38 patients with metastatic colorectal cancer. In this difficult-to-treat group, who had received a median of four prior lines of therapy, NUC-3373, with or without leucovorin, demonstrated a 62% disease control rate (defined as stable disease lasting more than 8 weeks) in the efficacy-evaluable population. Three patients experienced reductions in their target lesions of 40%, 28% and 15% and several patients achieved a longer progression-free survival on NUC-3373 than they had on their prior therapy. NUC-3373 also continues to demonstrate a favorable safety profile with no FBAL or FUTP-associated Grade 3 or 4 toxicities, such as hand-foot syndrome, GI or hematological adverse events.

Poster Title: NUC-3373-induced DAMPs release in CRC cells promotes natural killer cell activation

The second NUC-3373 poster showed that NUC-3373-treated colon cancer cells are able to activate a natural killer (NK) cell response. NUC-3373 was shown to induce the release of damage associated molecular patterns (DAMPs) which may restore NK cell-mediated immune responses by reducing inhibitory signals. Thus, NUC-3373 has the potential to evoke immunogenic cell death and may enhance the clinical utility of immunotherapy agents.

NUC-7738

NuCana presented two posters on NUC-7738, a ProTide transformation of a novel nucleoside analog, 3’-deoxyadenosine or 3’-dA. NUC-7738, which has several potential anti-cancer mechanisms of action, is being evaluated in a Phase I study in patients with advanced solid tumors who have exhausted all standard therapies.

Poster Title: NUC-7738, a novel ProTide transformation of 3’-deoxyadenosine, in patients with advanced solid tumors

The first poster describes additional interim data from the ongoing Phase I study. These data demonstrate NUC-7738’s encouraging anti-cancer activity and favorable tolerability profile. Three case studies were described detailing patients who achieved tumor reductions and prolonged stable disease on NUC-7738.

Poster Title: From bench to bedside: Using ProTide chemistry to transform 3’-deoxyadenosine into the novel anti-cancer agent NUC-7738

The second poster describes how NUC-7738 was designed to overcome the key cancer resistance mechanisms which have prevented the clinical development of 3’-dA. NUC-7738 was shown to efficiently generate high and prolonged intracellular levels of the active anti-cancer metabolite, 3’-dATP, and to cause cell death by activation of apoptotic pathways, as well as through inhibition of NFkB nuclear translocation.

Acelarin

Poster Title: NUC-1031 causes incorporation of fluorinated deoxycytidine into DNA, inducing persistent damage in biliary tract cancer cells

NuCana presented a poster that further demonstrated Acelarin’s activity in biliary tract cancer cells. Specifically, the poster described how Acelarin (NUC-1031) is converted to the active anti-cancer metabolite (dFdCTP) and demonstrated that it is incorporated into DNA, inducing persistent double-strand breaks. This leads to cell cycle arrest and DNA damage resulting in apoptosis in biliary tract cancer cells.

Abstracts and full session details can be found at www.aacr.org

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.

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!

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]).

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!

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 .

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!

"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]).

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!

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.