2026-27 Project (Chikh & Bennett)

p16-related designer peptides: a new strategy against melanoma

SUPERVISORY TEAM

Supervisor

Dr Anissa Chikh at City St George’s
School of Health & Medical Sciences, Department of Molecular and Biomedical Sciences
Email: achikh@citystgeorges.ac.uk

Co-Supervisor

Professor Dot Bennett at City St George’s
School of Health & Medical Sciences, Department of Molecular and Biomedical Sciences
Email: dbennett@citystgeorges.ac.uk

PROJECT SUMMARY

Project Summary

Melanoma (pigmented) skin cancer is a common cancer: mostly incurable and lethal at advanced stages. We seek a PhD student for a multidisciplinary project investigating a potential novel therapy, a “cell-penetrating peptide” or peptide modified to enter cells. The peptide is part of protein p16 (CDKN2A), a natural tumour-suppressor for melanoma. To date this peptide efficiently kills 5/5 advanced-melanoma cell lines yet excitingly shows little toxicity for normal cells (https://doi.org/10.1242/bio.059965). The student will further validate and optimize this peptide, aiming towards future preclinical and clinical testing. They will further test the selective toxicity, using further cultured normal and malignant cell types. They will test whether shorter fragments still work, and versions modified to be more stable in the body. They will investigate the mechanism of cell killing – the molecular target. They will learn incisive cellular and molecular techniques, in a research group with extensive experience in this field.

Project Key Words

Melanoma, therapy, designer-peptides, selectivity, target, cell-culture

MRC LID Themes

Translational and Implementation Research

Skills

MRC Core Skills

Interdisciplinary skills
Quantitative skills

Skills we expect a student to develop/acquire whilst pursuing this project:

Specialized cell culture: various human cancer and normal cell types
Assays for cell proliferation, migration and apoptosis (cell death)
Handling and design of cell-penetrating peptides • Cell transfection, RNA interference (siRNA)
Proximity ligation assays
qRT-PCR
Protein detection by immunoblotting and immunofluorescence
Advanced microscopic techniques for live and fixed cells
Background in melanoma/cancer biology, genetics and therapy
Teamwork skills
Statistical skills
Presentation skills (writing, oral data presentation)

Routes

Which route/s are available with this project?

1+4 = Yes
+4 = Yes

Possible Master’s programme options identified by supervisory team for 1+4 applicants:

City St Georges – MRes Biomedical Science – Clinical Biomedical Research
City St Georges – MRes Biomedical Science – Molecular Mechanisms of Cancer
City St Georges – MRes/MSc Translational Medicine
City St Georges – MSc Applied Biomedical Science
City St George’s – MSc Genomic Medicine

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? Yes

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution. At a minimum, all students must meet the institutional research degree regulations and expectations about onsite working and under this scheme they may be expected to work onsite (in-person) more frequently. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training for research degree study and training. Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Day-to-day work (primary location) for the duration of this research degree project will be at: City St George’s – Tooting campus, London

Travel requirements for this project: We will seek to arrange a 3-month placement probably in year 3 with a relevant UK-based commercial partner such as a manufacturer of synthetic peptides or cancer pharmaceuticals.

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

Minimum standard institutional eligibility criteria for doctoral study at City St George’s
First-class or 2(i) BSc or equivalent degree in a biomedical or biomolecular subject.
A good Masters degree would be advantageous.
Relevant laboratory experience preferable.

Other useful information

Potential Industrial CASE (iCASE) conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

Clinical relevance:
Melanoma (skin cancer of pigment cells/melanocytes) is the UK’s 5th commonest cancer, with a lifetime risk of ~1 in 38 (CRUK). Metastatic (advanced) melanoma is largely incurable and lethal. Despite recent advances in adjuvant and neoadjuvant therapies (targeted and immunotherapies), it still eventually recurs and kills most patients. Some melanoma cells must typically be resistant, and seed recurrence. A simultaneous co-therapy with a different molecular target might be able to kill these few resistant cells and prevent recurrence.

Research background:
This PhD project will follow up an initial study at St George’s (1) which raised the possibility of a novel and relatively safe therapy or co-therapy for metastatic melanoma. The study used a CPP (cell-penetrating peptide) designed by us, based on part of protein p16, product of the melanoma suppressor gene CDKN2A. Peptides are simply added to the cell culture medium for up to 5 days. The test peptide, called P16P1, achieved efficient, rapid, dose-dependent apoptotic killing of 3/3 human metastatic melanoma cell lines tested (1) (5/5 with further unpublished work), yet (remarkably) with no effect at all on normal human fibroblasts. Normal human melanocytes (2 lines) were also spared except at the highest dose tested. HeLa cervical cancer cells were also efficiently killed, and there was varying toxicity towards other cancer cell types. The toxicity was highly sequence-specific and required entry into cells (1).

Logistics:
The MRC-LID student will work to validate further and optimize this peptide in vitro, required before preclinical and clinical testing.

The selectivity of P16P1 will be investigated more broadly, testing the peptide’s toxicity on further normal human cell types (keratinocytes, endothelial cells etc) and other cancer cell lines. The core assays will be cell counts (viability) and assays for apoptotic markers. We will also use the Livecyte video system at CSG, quantitating cell proliferation, migration and death.
The peptide will be optimized further for retained or increased activity and selectivity (malignant vs. normal cells) by varying the sequence, especially testing a potentially active shorter (and therefore cheaper) form. This section will use one highly metastatic melanoma line, with positive findings validated on other lines and selectivity (sparing of normal cells) rechecked.
Importantly for any commercial interest, the student will investigate the target and mechanism of action. Evidence indicates that CDK4, the canonical target of full-length p16, is not the main target for P16P11. Other published p16-binding partners will be tested for peptide binding and mediation of the toxic effect, by methods including proximity ligase assays and siRNA interference. Other techniques used here will include immunoblotting and immunofluorescence. A global screen may be used if necessary, such as a phospho-proteome array screen.
Because normal peptides are broken down in the bloodstream, the student will test (for retained selective toxicity) one or more modified forms of the optimized peptide that will be more stable in vivo, such as the “retro-inverso” form. This will lay groundwork towards preclinical and clinical testing.

(1) Soo JK et al. (2023); see DOI below.

Additional information from the supervisory team

The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.

Chikh & Bennett Recording

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