Dr Alan Richardson

Title: Reader in Pharmacology
Phone: +44 (0)1782 674424
Email: a.richardson1@keele.ac.uk
Location: Institute for Science & Technology in Medicine, Keele University,
Guy Hilton Research Centre, Thornburrow Drive, Hartshill, Stoke-on-Trent ST4 7QB United Kingdom
Role: ISTM Research theme: Therapeutics (Theme lead)
Contacting me: By phone or email
Alan_Richardson_193x200_2

Following a PhD and post-doctoral work in pharmacology at Cambridge, Alan completed his post-doctoral training at the University of Virginia, USA. Following several years leading drug discovery programs in industry (Johnson & Johnson, Belgium and OSI pharmaceuticals, Oxford) he returned to academic research at the Institute of Cancer Research in London. At Keele, he is module leader and a lecturer on three pharmacology modules and a final year module option on oncology molecular therapeutics. He also makes teaching contributions to the School of Life Sciences and the School of Medicine. He is currently second year tutor.  His research interests focus on discovering new therapeutic targets and drugs for the treatment of ovarian cancer. He has received funding from charities and Research Councils.

ISTM Research theme: Therapeutics

Research interests:

The goal of research in my group is to help discover new treatments for cancer. A major focus of my group is ovarian cancer, but we are beginning to apply our results to other cancer types.

The fundamental research performed into cancer biology over the last 30 years or so has been translated into new therapies that are now becoming available to treat patients. These “targeted therapies” differ from most traditional chemotherapy by exploiting specific defects in cancer cells. Cancer cells may become overly dependent on one particular signalling pathway, and so are susceptible to drugs that target those pathways. Non-cancerous cells which are less dependent on these pathways are consequently less sensitive to the effects of the targeted therapies. As a consequence, targeted therapies often have milder side effects than traditional chemotherapy.

In some cases, targeted therapies have been very successful, but in other cases the drugs have not been as successful as originally hoped. There are several reasons for this. One of the key reasons is that tumours are heterogeneous – the cells in tumours are not all the same and different cancer cells may be driven by different defects. Consequently, one drug targeting   a single defect may not be able to kill all the cancer cells in the tumour.  A second reason for some drugs underperforming is that the cancer cells can “evolve”. Cancer cells can mutate and become resistant to a particular targeted therapeutic drug. This gives the cells with the mutation a selective advantage because cells with the mutation continue to grow in the presence of the drug while cells without the drug are killed.  A third reason is that tumours may be caused by defects in several pathways, so a targeted therapeutic drug that inhibits a single pathway may not be sufficient to kill the cancer cells.

The diagram shows the why cancer therapies may fail. Cancer cells (blue circles) maybe sensitive to therapeutic drugs, but other (red circles) may be resistant.

There are several potential solutions to these problems. One is to use combinations of drugs which inhibit several pathways at the same time. Another solution is to target essential cellular processes that are used by a large proportion of the cancer cells. Lastly, it may be possible to find drugs which make traditional chemotherapy more effective. Research in my group is making use of all these strategies.

Statins

Statins inhibit HMGCR, an enzyme involved in the biosynthesis of cholesterol and isoprenoids. There are numerous reports that statins can kill cancer cells in the laboratory, and studies looking at patients taking statins control their cholesterol also hint at a reduced risk of cancer. However, when statins have been tested in prospective clinical trials in cancer, they have so far largely been unimpressive. We have found three reasons that are likely to explain why these trials have failed in the past and, importantly, how clinical trials should be designed in the future to overcome these problems.

  1. Pitavastatin is a unique statin which is more likely than other statins to be successful as a cancer treatment. It is the only statin which is both hydrophobic (which makes the drug potent) and has a sufficiently long half-life to allow continual inhibition of HMGCR with a reasonable interval between doses.
  2. A suitable dosing regimen needs to be used.  Relatively high doses of pitavastatin are likely to be necessary. The dose of statins used to treat elevated cholesterol does not provide a sufficiently high drug concentration to kill cancer cells. The interval between doses needs to maintain continual inhibition of HMGCR (Robinson et al) and in the case of pitavastatin this can be achieved with twice daily dosing. This regimen brings with it a risk of causing myopathy which needs to be monitored.
  3. Diet needs to be controlled. Statins kill cancer cells by preventing the production of geranylgeraniol but this is found in some foods, bypassing the effect of the statins. “Ensure” is one potential food replacement that lacks geranylgeraniol and which patients could use while receiving pitavastatin therapy.

    When all the factors are taken into account, we have shown that we can cause regression of tumours in mice (deWolf et al).

 

The diagram (left) shows regression of Ovcar-4 tumours in mice treated with pitavastatin and on a diet of “Ensure”.  The second diagram (right) shows that if the diet contains geranylgeraniol, pitavastatin no longer shrinks the tumour.  From deWolf et al.

Autophagy

Autophagy is the process by which cells can recycle damaged cellular components. Cancer cells use autophagy to survive nutrient deprivation, hypoxia and low pH and they can also become dependent on autophagy for survival under oncogenic stress. Several studies have also demonstrated that pharmacological or genetic inhibition of autophagy sensitises cells to anti-cancer drugs. We are focusing on a key step in autophagy, the formation of a complex between Atg16 and Atg5 (shown in the figure). We have developed novel autophagy assays and this has allowed us to identify compounds which inhibit the interaction of Atg5-Atg16 interaction. We are currently optimizing these compounds with the goal that these will subsequently be tested in patients with cancer.

 

The diagram shows the interaction of Atg5 (magenta) and Atg 16 (yellow) Data from Kim et al.

 

Overcoming resistance to chemotherapy

One of the barriers to the successful treatment of cancer patients with chemotherapy is that the tumours can evolve to become resistant to the drugs. We have previously conducted a RNAi screen to identify genes which confer resistance to carboplatin and paclitaxel (Vidot et al), drugs commonly used to treat ovarian cancer. One of the genes we identified in the screen was autotaxin. We have gone on to develop novel delivery strategies for drugs that inhibit autotaxin (Fisher et al).  

 

 

The diagram shows the effect of knockdown of 90 different genes, known to be over-expressed in ovarian cancer, on the sensitivity of 6 different cell lines to carboplatin (“C”) and paclitaxel (T). Data from Vidot et al.

We are currently evaluating other potential drug targets identified by this screen one of which is a protein regulating metabolism and we have identified novel inhibitors.  We plan to optimize these compounds for subsequent evaluation in clinical trials.

Public outreach

I have created the “Why do scientists do what scientists do” website to explain to a lay audience some of the things scientists get up to. It is also a useful introduction of students of science.

Collaborators

Steve Allin,  Charnwood Molecular

Mike Edwards Keele University

Clare Hoskins, Keele University

Darren Moss, Keele University

Melissa Mather, Keele University

Johannes Reynisson, University of Auckland

Farhat Khanim, Birmingham University

Funding

Funding for work in our group has been gratefully received from:

Medical Research Council

Wellcome Trust

The Higher council for education development in Iraq

Ministry of Higher Education and Scientific Research (Iraq)

Keele University

The North Staffordshire Medical Institute.

We welcome offers of funding to support our research – nationally, only 10-20% of grant applications are currently funded. If you would like to contribute to our research to discover new cancer treatments, please click here and then on the donations tab. Donations may be tax deductible. If you would like your donation to specifically fund our research rather than research in our Institute in general, please notify the contact listed there. Thank you!

 

 

Selected Publications

  • Robinson E, Nandi M, Wilkinson LL, Arrowsmith DM, Curtis ADM, Richardson A. 2013. Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecol Oncol, vol. 129(2), 417-424. link> doi>
  • Stamelos VA, Robinson E, Redman CW, Richardson A. 2013. Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells. Gynecol Oncol, vol. 128(2), 377-382. link> doi>
  • Richardson A, Underwood JK, Allin SM, Redman CW. 2012. Autotaxin - a target for the treatment of drug-resistant ovarian cancer?. In Ovarian cancer - basic science perspective. Farghaly S (Ed.). (vol. 1). Intech. link>
  • Stamelos VA, Redman CW, Richardson A. 2012. Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine. J Mol Signal, vol. 7(1), 12. link> doi>
  • Vidot S, Witham J, Agarwal R, Greenhough S, Bamrah HS, Tigyi GJ, Kaye SB, Richardson A. 2010. Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells. CELLULAR SIGNALLING, vol. 22(6), 926-935. link> doi>

Full Publications List show

Journal Articles

  • Abdullah MI, Abed MN, Richardson A. 2017. Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells. Sci Rep, vol. 7(1), 8090. link> doi>
  • de Wolf E, Abdullah MI, Jones SM, Menezes K, Moss DM, Drijfhout FP, Hart SR, Hoskins C, Stronach EA, Richardson A. 2017. Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer. Sci Rep, vol. 7(1), 5410. link> doi>
  • Robinson E, Jones S, Menezes K, Abdullah M, Stronach E, Hoskins C, Richardson A. 2016. Pitavastatin is a potential treatment for drug-resistant ovarian cancer. European Journal of Cancer, vol. 61(1), 192. doi> link>
  • Uche FI, Drijfhout FP, McCullagh J, Richardson A, Li W-W. 2016. Cytotoxicity Effects and Apoptosis Induction by Bisbenzylisoquinoline Alkaloids from Triclisia subcordata. Phytother Res, vol. 30(9), 1533-1539. link> doi>
  • Abed MN, Abdullah MI, Richardson A. 2016. Antagonism of Bcl-XL is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells. J Ovarian Res, vol. 9, 25. link> doi>
  • Stamelos VA, Fisher N, Bamrah H, Voisey C, Price JC, Farrell WE, Redman CW, Richardson A. 2016. The BH3 Mimetic Obatoclax Accumulates in Lysosomes and Causes Their Alkalinization. PloS one, vol. 11(3), e0150696. doi>
  • Kitchen MO, Yacqub-Usman K, Emes RD, Richardson A, Clayton RN, Farrell WE. 2015. Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells. Pituitary, vol. 18(5), 674-684. link> doi>
  • Johnson-Ajinwo OR, Richardson A, Li W-W. 2015. Cytotoxic effects of stem bark extracts and pure compounds from Margaritaria discoidea on human ovarian cancer cell lines. Phytomedicine, vol. 22(1), 1-4. link> doi>
  • Richardson A, Curtis ADM, Moss GP, Pearson RJ, White S, Rutten FJM, Perumal D, Maddock K. 2014. Simulated drug discovery process to conduct a synoptic assessment of pharmacy students. Am J Pharm Educ, vol. 78(2), 41. link> doi>
  • Robinson E, Fisher N, Stamelos V, Redman C, Richardson A. 2014. New strategies for the treatment of ovarian cancer. Biochem Soc Trans, vol. 42(1), 125-129. link> doi>
  • Fisher N, Hilton-Bolt T, Edwards MG, Haxton KJ, McKenzie M, Allin SM, Richardson A. 2014. Dendrimer Conjugate of [4-(Tetradecanoylamino)benzyl]phosphonic Acid (S32826) as an Autotaxin Inhibitor. ACS Med Chem Lett, vol. 5(1), 34-39. link> doi>
  • Jain HV, Richardson A, Meyer-Hermann M, Byrne HM. 2014. Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. PLoS One, vol. 9(1), e81582. link> doi>
  • Fisher N, Edwards M, Allin S, Richardson A. 2013. AUTOTAXIN INHIBITORS AS A POTENTIAL TREATMENT FOR OVARIAN. INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, vol. 23(8). link>
  • Richardson A and Robinson E. 2013. THE POTENTIAL FOR STATINS IN THE TREATMENT OF OVARIAN CANCER. INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, vol. 23(8). link>
  • Maddock K. 2013. Chairs, bells and students – a novel method to simulate and teach molecular interactions in pharmacology. Pharmacy Education, vol. 13, 36-39. link>
  • Robinson E, Nandi M, Wilkinson L, Arrowsmith M, Curtis ADM, Richardson A. 2013. Preclinical Evaluation of Statins as a Treatment for Ovarian Cancer. Gynecologic Oncology, vol. 129, 417-424. doi>
  • Robinson E, Nandi M, Wilkinson LL, Arrowsmith DM, Curtis ADM, Richardson A. 2013. Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecol Oncol, vol. 129(2), 417-424. link> doi>
  • Richarson A, Bracegirdle L, McLachlan SIH, Chapman SR. 2013. Use of a Three-Dimensional Virtual Environment to Teach Drug-Receptor Interactions. American Journal of Pharmaceutical Education, vol. 77(1), Article 11. doi> link>
  • Richardson A and Robinson E. 2013. The potential for statins in the treatment of ovarian cancer. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol. 32, S67. link>
  • Stamelos VA, Robinson E, Redman CW, Richardson A. 2013. Navitoclax augments the activity of carboplatin and paclitaxel combinations in ovarian cancer cells. Gynecol Oncol, vol. 128(2), 377-382. link> doi>
  • Yacqub-Usman K, Richardson A, Duong CV, Clayton RN, Farrell WE. 2012. The pituitary tumour epigenome: aberrations and prospects for targeted therapy. Nat Rev Endocrinol, vol. 8(8), 486-494. link> doi>
  • Stamelos VA, Redman CW, Richardson A. 2012. Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine. J Mol Signal, vol. 7(1), 12. link> doi>
  • Al-Azzawi H, Yacqub-Usman K, Richardson A, Hofland LJ, Clayton RN, Farrell WE. 2011. Reversal of endogenous dopamine receptor silencing in pituitary cells augments receptor-mediated apoptosis. Endocrinology, vol. 152(2), 364-373. link> doi>
  • Vidot S, Witham J, Agarwal R, Greenhough S, Bamrah HS, Tigyi GJ, Kaye SB, Richardson A. 2010. Autotaxin delays apoptosis induced by carboplatin in ovarian cancer cells. CELLULAR SIGNALLING, vol. 22(6), 926-935. link> doi>
  • Rowther FB, Richardson A, Clayton RN, Farrell WE. 2010. Bromocriptine and dopamine mediate independent and synergistic apoptotic pathways in pituitary cells. Neuroendocrinology, vol. 91(3), 256-267. link> doi>
  • Richardson A and Kaye SB. 2008. Pharmacological inhibition of the Bcl-2 family of apoptosis regulators as cancer therapy. Curr Mol Pharmacol, vol. 1(3), 244-254. link> doi>
  • Witham J, Vidot S, Kaye SB, Richardson A. 2008. Transient ectopic expression as a method to detect genes conferring drug resistance. International Journal of Cancer, vol. 122, 2641-2645. doi>
  • Witham J, Valenti M, De-Haven Brandon A, Vidot S, Eccles S, Kaye S, Richardson A. 2007. The Bcl-2/Bcl-XL Family Inhibitor ABT-737 Sensitizes Ovarian Cancer Cells to Carboplatin. Clinical Cancer Research, vol. 13, 7198. doi>
  • Mortier E, Cornelissen F, van Hove C, Dillen L, Richardson A. 2001. The focal adhesion targeting sequence is the major inhibitory moiety of Fak-related non-kinase. CELLULAR SIGNALLING, vol. 13(12), 901-909. link> doi>
  • Ma A, Richardson A, Schaefer EM, Parsons JT. 2001. Serine phosphorylation of focal adhesion kinase in interphase and mitosis: A possible role in modulating binding to p130(Cas). MOLECULAR BIOLOGY OF THE CELL, vol. 12(1), 1-12. link> doi>
  • Masure S, Haefner B, Wesselink JJ, Hoefnagel E, Mortier E, Verhasselt P, Tuytelaars A, Gordon R, Richardson A. 1999. Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. EUROPEAN JOURNAL OF BIOCHEMISTRY, vol. 265(1), 353-360. link> doi>
  • Taylor JM, Richardson A, Parsons JT. 1998. Modular domains of focal adhesion-associated proteins. PROTEIN MODULES IN SIGNAL TRANSDUCTION, vol. 228, 135-163. link>
  • Richardson A, Malik RK, Hildebrand JD, Parsons JT. 1997. Inhibition of cell spreading by expression of the C-terminal domain of focal adhesion kinase (FAK) is rescued by coexpression of Src or catalytically inactive FAK: A role for paxillin tyrosine phosphorylation. MOLECULAR AND CELLULAR BIOLOGY, vol. 17(12), 6906-6914. link> doi>
  • Richardson A, Shannon JD, Adams RB, Schaller MD, Parsons T. 1997. Identification of integrin-stimulated sites of serine phosphorylation in FRNK, the separately expressed C-terminal domain of focal adhesion kinase: A potential role for protein kinase A. BIOCHEMICAL JOURNAL, vol. 324, 141-149. link> doi>
  • Burnham MR, Harte MT, Richardson A, Parsons JT, Bouton AH. 1996. The identification of p130(cas)-binding proteins and their role in cellular transformation. ONCOGENE, vol. 12(11), 2467-2472. link>
  • Richardson A and Parsons JT. 1996. A mechanism for regulation of the adhesion-associated protein tyrosine kinase pp125(FAK). NATURE, vol. 380(6574), 538-540. link> doi>
  • Parsons JT, Richardson A, Hildebrand J, Harte M, Bouton A. 1996. Focal adhesion-associated kinases and cell signalling. JOURNAL OF NEUROCHEMISTRY, vol. 66, S7. link>
  • RICHARDSON A and PARSONS JT. 1995. SIGNAL-TRANSDUCTION THROUGH INTEGRINS - A CENTRAL ROLE FOR FOCAL ADHESION KINASE. BIOESSAYS, vol. 17(3), 229-236. link> doi>
  • RICHARDSON A and TAYLOR CW. 1993. EFFECTS OF CA2+ CHELATORS ON PURIFIED INOSITOL 1,4,5-TRISPHOSPHATE (INSP3) RECEPTORS AND INSP3-STIMULATED CA2+ MOBILIZATION. JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 268(16), 11528-11533. link>
  • OLDERSHAW KA, RICHARDSON A, TAYLOR CW. 1992. PROLONGED EXPOSURE TO INOSITOL 1,4,5-TRISPHOSPHATE DOES NOT CAUSE INTRINSIC DESENSITIZATION OF THE INTRACELLULAR CA2+-MOBILIZING RECEPTOR. JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 267(23), 16312-16316. link>
  • RICHARDSON A, SIMON J, BARNARD EA. 1992. PROTECTION BY OPIOID LIGANDS AGAINST MODIFICATION OF THE OPIOID RECEPTOR BY A CARBODIIMIDE. BIOCHEMICAL PHARMACOLOGY, vol. 43(7), 1415-1419. link> doi>
  • TAYLOR CW and RICHARDSON A. 1991. STRUCTURE AND FUNCTION OF INOSITOL TRISPHOSPHATE RECEPTORS. PHARMACOLOGY & THERAPEUTICS, vol. 51(1), 97-137. link> doi>
  • Li WW, Rosa JO, Siddique MR, Bajana B, Sule-Suso J, Richardson A. 2013. Anti-cancer thymoquinone from Nigella sativa. PLANTA MEDICA, vol. 79(13), 1126. link>
  • PARSONS JT, SCHALLER MD, HILDEBRAND J, LEU TH, RICHARDSON A, OTEY C. 1994. FOCAL ADHESION KINASE - STRUCTURE AND SIGNALING. JOURNAL OF CELL SCIENCE, 109-113. link>
  • Richardson A, Demoliou-Mason C, Barnard EA. Guanine nucleotide-binding protein-coupled and -uncoupled states of opioid receptors and their relevance to the determination of subtypes. Proceedings of the National Academy of Sciences of USA, vol. 89(21), 10198-10202. link>
  • Richardson A and Taylor C. 1992. Purification of the inositol1,4,5-trisphosphate receptor by heparin affinity chromatography using decavandate. Biochem Soc Trans, vol. 20(2), 135S. link> doi>
  • Robinson E, Leung E, Matuszek AM, Krogsgaard-Larsen N, Furkert DP, Brimble MA, Richardson A, Reynisson J. 2015. Virtual screening for novel Atg5-Atg16 complex inhibitors for autophagy modulation. MEDCHEMCOMM, vol. 6(1), 239-246. link> doi>

Chapters

  • Richardson A, Underwood JK, Allin SM, Redman CW. 2012. Autotaxin - a target for the treatment of drug-resistant ovarian cancer?. In Ovarian cancer - basic science perspective. Farghaly S (Ed.). (vol. 1). Intech. link>

Other

  • Johnson-Ajinwo OR, Richardson A, Li W-W. 2017. Identification and evaluation of anticancer compounds from three Nigerian plants used in traditional medicines. BIOCHEMICAL PHARMACOLOGY (vol. 139, p. 128). link> doi>
  • Uche FI, Abed M, Abdullah MI, Drijfhout FP, McCullagh J, Claridge TWD, Richardson A, Li W-W. 2017. Isolation, identification and anti-cancer activity of minor alkaloids from Triclisia subcordata Oliv. BIOCHEMICAL PHARMACOLOGY (vol. 139, p. 112). link> doi>
  • Uche F, Abed M, Abdullah M, Drijfhout FP, McCullagh J, Claridge T, Richardson A, Li WW. 2017. O9 Isolation, identification and anti-cancer activity of minor alkaloids from Triclisia subcordata Oliv. Biochemical Pharmacology (vol. 139). Elsevier BV. doi> link>
  • Johnson-Ajinwo OR, Richardson A, Li WW. 2017. P11 Identification and evaluation of anticancer compounds from three Nigerian plants used in traditional medicines. Biochemical Pharmacology (vol. 139, p. 128). Elsevier BV. doi> link>
  • Abed MN and Richardson A. 2016. Inhibition of BCKDK increases the sensitivity of ovarian cancer cells to paclitaxel. EUROPEAN JOURNAL OF CANCER (vol. 69, p. S20). link> doi>
  • Robinson E, Abdullah M, Jones S, Menezes K, Euan S, Hoskins C, Richardson A. 2016. Preclinical evaluation of pitavastatin as a treatment for chemotherapy-resistant ovarian cancer. EUROPEAN JOURNAL OF CANCER (vol. 69, p. S150). link> doi>
  • Uche FI, Li WW, Richardson A, Greenhough TJ. 2014. Anticancer activities of cyclotides from Viola yedeonsis Makino (Violaceae). PLANTA MEDICA (vol. 80, p. 818). link>
  • Uche F, Li WW, Richardson A, Greenhough TJ. 2014. Anti-ovarian cancer activities of alkaloids from Triclisia subcordata olive (Menispermecaea). PLANTA MEDICA (vol. 80, p. 813). link>
  • Richardson M, Robinson E, Turner C, Allin S, Richardson A, Pearson R. 2012. Novel heterocyclic NO-donors as potential anti-cancer agents. NITRIC OXIDE-BIOLOGY AND CHEMISTRY (vol. 27, p. S37). link> doi>
  • Richardson A. 3- phenyl analogs of toxoflavine as kinase inhibitors.
  • Richardson A. 3-furanyl analogs of toxoflavine as kinase inhibitors.
  • Richardson A. Human Akt-3.