A phase I dose-escalation study of the novel peptide ALM201 in patients (pts) with advanced solid tumours

Helali, Aya El; Plummer, Ruth; Jayson, Gordon C; Coyle, Victoria; Drew, Yvette; Mescallado, Nerissa; Harris, Neil; Clamp, A; McCann, John; Kennedy, Richard L.; Cranston, Aaron; Wilson, Richard H.

doi:10.1093/annonc/mdx367.017

Cited by 8 publications

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“…This triple therapeutic action will undoubtedly provide added clinical benefit as it progresses through clinical development. Based on robust pre-clinical efficacy, without associated toxicity, ALM201 entered a 'first in man' clinical trial in oncology, where unlike other anti-angiogenics, it is not cytotoxic and displayed an excellent safety profile in this Phase I clinical trial [27].…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of CD44 is associated with angiogenesis, stemness, tumourigenicity and cell migration [26]. The 'first-in-class' FKBPL-based peptides, AD-01 (24-amino acid pre-clinical therapeutic candidate) and ALM201 (23-amino acid clinical therapeutic candidate which has successfully completed a Phase Ia clinical trial [EudraCT 2014-001175-31]) [27], have also demonstrated strong anti-angiogenic and anti-CSC effects [5,24,25]. The anti-CSC activity of AD-01 led to downregulation of stem cell markers, Nanog, Oct4 and Sox2 in breast cancer cell lines while the intratumoural knockdown of FKBPL in a ZR-75 breast cancer xenograft mouse model increased the expression of Nanog/, Oct4 and Sox2 [5]; Sox2 has been implicated in both metastasis and endocrine therapy resistance [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

et al. 2019

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Background: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER-and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER-MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. Results: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, preclinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER-breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

et al. 2019

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“…As a FK506 binding protein like (FKBPL) peptide derivative, ALM-201 can bind to CD44 and inhibit cancer related pathways, such as DLL4/NOTCH signal pathway as well as inhibit cell migration, tubule formation and angiogenesis. ALM-201 showed an excellent safety profile and acceptable PK in patients with advanced solid tumors in a phase I dose-escalation study (39). This candidate is currently in phase I clinical trials for the treatment of patients with advanced ovarian cancer and other solid tumors (33).…”

Section: Therapeutic Targeting Of Cscsmentioning

confidence: 99%

Current Advance of Therapeutic Agents in Clinical Trials Potentially Targeting Tumor Plasticity

et al. 2019

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Tumor plasticity refers to tumor cell's inherent property of transforming one type of cell to different types of cells. Tumor plasticity is the main cause of tumor relapse, metastasis and drug resistance. Cancer stem cell (CSC) model embodies the trait of tumor plasticity. During carcinoma progression, epithelial-mesenchymal transition (EMT) plays crucial role in the formation of CSCs and vasculogenic mimicry (VM) based on epithelial-mesenchymal plasticity. And the unique tumor microenvironment (TME) not only provides suitable niche for CSCs but promotes the building of CSCs and VM that nourishes tumor tissue together with neoplasm metabolism by affecting tumor plasticity. Therapeutic strategies targeting tumor plasticity are promising ways to treat malignant tumor. In this article, we discuss the recent developments of potential drug targets related to CSCs, EMT, TME, VM, and metabolic pathways and summarize drugs that target these areas in clinical trials.

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“…Analysis of the structure, activity and stability of AD-01 led to the selection of ALM201, a 23 residue peptide as the clinical drug candidate. ALM201 lacks cytotoxicity and displayed a very good safety profile in a Phase I, first-in-man, dose-escalation clinical trial in patients with ovarian cancer and other solid tumours (EudraCT number: 2014-001175-31) (28,29). Furthermore, ALM201 designated orphan drug status by the FDA in ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

“…ALM201 lacks cytotoxicity and displayed a very good safety profile in a Phase I, first-in-man, dose-escalation clinical trial in patients with ovarian cancer and other solid tumours (EudraCT number: 2014-001175-31). 27 , 28 Furthermore, ALM201 was designated orphan drug status by the FDA in ovarian cancer. Given that anti-angiogenic agents are demonstrating efficacy in the HGSOC setting, a disease of unmet clinical need, we assessed whether ALM201 could elicit dual anti-angiogenic and anti-stemness activity in this disease.…”

Section: Introductionmentioning

confidence: 99%

FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer

et al. 2019

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Background ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. Methods In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). Results ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. Conclusion FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

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A phase I dose-escalation study of the novel peptide ALM201 in patients (pts) with advanced solid tumours

Cited by 8 publications

References 0 publications

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

Current Advance of Therapeutic Agents in Clinical Trials Potentially Targeting Tumor Plasticity

FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer

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