In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress.

PTK7 has been identified as a potential therapeutic target, and a PTK7 antibody drug conjugate (PF-06647020; cofetuzumab pelidotin) has been investigated in phase I clinical trials for triple-negative breast cancer, ovarian cancer, and non-small cell lung cancer...PTK7 protein and mRNA expression were associated with breast cancer-specific survival of patients with a poor prognostic Nottingham Prognostic Index (NPI) and a moderate prognostic NPI, respectively. Taken together, these data indicate that PTK7 expression is associated with patient outcome in subgroups of breast cancer patients.

P1, N=65, Active, not recruiting, AbbVie | Phase classification: P1b --> P1 | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Feb 2024 --> Dec 2024

Moreover, PTK7-targeting strategies based on antibody-drug conjugates, aptamers, and CAR-T cell-based therapies have demonstrated encouraging results in preclinical and clinical settings. We review the most recent data assigning to PTK7 a prominent role in cancer progression as well as current preclinical and clinical targeting strategies against RTK family pseudokinases including PTK7.

P1/2, N=214, Recruiting, ProfoundBio US Co. | Not yet recruiting --> Recruiting

P1/2, N=214, Not yet recruiting, ProfoundBio US Co.

Although the TROP2-targeting ADC sacituzumab govitecan was recently granted accelerated approval from the FDA for treating patients with metastatic TNBC,1 the on-target toxicity of this single-targeting agent has limited clinical efficacy. Conclusions BCG033 is a novel bispecific antibody-drug conjugate that targets PTK7 and TROP2. BCG033 demonstrates promising preclinical efficacy in vivo, suggesting it may offer new treatment options for TNBC or other solid tumors expressing PTK7 and TROP2 in the future.

In summary, our study opens the door for further evaluation of ADCs in several indications not explored before.

Further validation is warranted in terms of protein expression. Our results underscore the potential value of gene expression profiling to identify new targets and improve patient selection in the context of NSCLC-BM ADC therapy.

CI, confidence intervals; CBR, clinical benefit rate; CR, complete response; EGFR, epidermal growth factor; mDOR, median duration of response; mPFS, median progression free survival; NSQ, nonsquamous; ORR, objective response rate; PR, partial response; PTK7, protein tyrosine kinase 7; pts, patients; SD, stable disease; WT, wild type. Conclusions Cofe-P was well-tolerated with encouraging antitumor activity observed in rNSCLC and 30% ORR in the subpopulation with NSQ EGFR WT NSCLC and PTK7 ≥90%/≥2+.

P1b, N=65, Active, not recruiting, AbbVie | Trial completion date: Nov 2023 --> Feb 2024 | Trial primary completion date: Nov 2023 --> Feb 2024

When using a potent microtubule inhibitor (Aur0101), PTK7-targeting antibody-drug conjugate (ADC), h6M24-vc0101 (PF-06647020/Cofetuzumab pelidotin) is efficacious only in limited tumor types with low response rates in a phase I trial...MTX-13 displayed a favorable pharmacokinetic and safety profile in monkey with a highest non-severely toxic dose (HNSTD) of >30 mg/kg, significantly higher than 3-5 mg/kg of HNSTD for h6M24-vc0101. The higher therapeutic index of MTX-13 bodes well for its clinical translation with a potential to expand responding patient population beyond that of current PTK7-targeting ADCs.

P1b, N=65, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting

Recently, the TROP2-targeting ADC sacituzumab govitecan has received an accelerated approval from the FDA for adult patients with metastatic TNBC, as more than 85% of TNBC is marked by TROP2 overexpression. Patient-derived TNBC xenografts with co-expression of PTK7 and TROP2 have been screened for future in vivo drug efficacy screening. In summary, BCG033 has the potential to exert anti-tumor efficacy in TNBC and other solid tumors co-expressing PTK7 and TROP2.

Currently, early-phase trials of ADCs in non-small cell lung cancer are rapidly gaining ground, with promising results targeting HER2 (human epidermal growth factor 2), HER3, TROP2 (trophoblast cell surface antigen 2), MET, CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5), and PTK7 (tyrosine protein kinase-like 7). Unfortunately, in small cell lung cancer, trials targeting the ubiquitous DLL3 (delta-like ligand 3) protein have failed to show clinically relevant results, despite significant toxicity.

The combination of gedatolisib + cofetuzumab pelidotin was well tolerated and demonstrated promising clinical activity. Further investigation of this drug combination in metastatic TNBC is warranted.

Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla, Enhertu, Trodelvy, and Abraxane)...In TNBC these conjugates (Trodelvy, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody-drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed.

We also summarize the clinical development of several promising ADCs in early phase clinical trials for the treatment NSCLC. including ADCs against well-established targets (e.g.HER2 in breast cancer, Nectin4 in urothelial cancer), novel antigenic targets (e.g. HER3, TROP2, PTK7, CEACAM5), as well as promising combinations with agents known to be active in NSCLC such as tyrosine kinase inhibitors and ICI therapy, as a strategy to overcome mechanisms of resistance to ADC therapy.

Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat and others) and antibody‑based biologics targeting Notch ligands or receptors [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) and others] have been developed as investigational drugs...Phase III clinical trials of Rova‑T for patients with small‑cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted therapy for patients with cancer.