Bacteria in cancer therapy
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Transcript of Bacteria in cancer therapy
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BACTERIA IN CANCER THERAPY
Presented by – GAURAV GANGWAR
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INTRODUCTION • Therapies like photodynamic therapy,
HAMLET(human alpha-lactalbumin made lethal to tumor cell), gene therapy, complementary and alternative therapy etc. are intended or claimed to treat cancer.
• But a Live, attenuated, genetically modified, non-pathogenic bacterial species and bacterial spores are also capable of inhibiting the growth of cancer.
• The most potential and promising strategy is bacteria based gene-directed enzyme prodrug therapy.
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HISTORY • Observation of German physicians W. busch &
F. fehleisen..• American physician William coley. ‘coley’s toxins’ – Two heat killed bacterial
species, Salmonella pyogenes and serratia marcescens.
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BACTERIAL TARGET OF TUMOR• Obligate anaerobes (e.g Clostridium and
bifidobacterium) - target the anoxic area of tumor, and inhibit
the growth of tumor.• Facultative anaerobes (e.g. Salmonella and
Escherichia)• - identify and penetrate tumors by detecting
and chemotaxising towards small molecule gradients of serine, aspartate and ribose.
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BACTERIA AS TUMORICIDAL AGENT• Clostridium novyi–NT (attenuated clostridium strain) produce toxicity
in tumor even after deletion of genes coding for a lethal toxin.• COBALT(combination bacteriolytic therapy)- Clostridium novyi-NT
spores were administered in combination with conventional chemotherapeutic agents like dolastatin-10, mitomycin C, vinorelbine and docetaxel.
• Bacillus Calmette Guerin(BCG),the most successful bacterial agent so far is used specifically for the treatment of superficial bladder cancer
• Salmonella strain VNP20009-after deletion of two genes msb & purl results in its complete attenuation.
-VNP20009 has been successfully investigated in phase 1 clinical trials in cancer patients.
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BACTERIA AS VECTOR FOR GENE THERAPY AND TUMORICIDAL AGENT
• For delivering anticancer agents, cytotoxic peptides, therapeutics protein or produrg converting enzymes.
e.g. Salmonella • Two reports showed that when transfer of anti-
angiogenic genes (thrombospondin and endostain) from salmonella, prevent the formations of new blood vessel and stopped the nutrient supply in tumor cell.
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• Attenuated selmonella typhimurium- used to deliver cytokines(IL-2) locally to liver cancer.
• Various therapeutic proteins, including TNF-alpha and platelet factor 4 fragment, have been cloned and expressed in VNP20009.
• Bifidobacterium adolescentis spore administration via tail vein of tumor-bearing mice resulted in strong inhibition of angiogenesis.
• Functional TNF- alpha has been cloned and expressed in C. acetobutylicum.
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BACTERIA DIRECTED ENZYME PRODURG THERAPY
• Cytosine deaminase (CD) have been successfully expressed in C. sporogenes and C. acetobutylicum.
-convert 5-fluorocytosine(5FC) to 5-fluorouracil(5FC).• Salmonella vector has also been combined with CD and
nitroreductase, and success has been observed in vivo and it is currently undergoing in phase 1 clinical trials.
• TAPET(Tumor Amplified Protein Expression Therapy) uses VNP20009 expresses an E.coli CD for preferentially delivering anti-cancer drug to solid tumor.
• Salmonella + carboxypeptidase G2(enzyme convert mustard prodrug to DNA cross-linking agent) show significant results in vivo.
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BACTERIAL TOXINS FOR CANCER• Cyclomodulins- bacterial toxins that subvert the host eukaryotic cell
cycle. E.g. 1. CNF(from E.coli) –cytotoxic necrosis factors, a cell-cycle
stimulator. - triggers the G1 - S transition and induces DNA replication.
2. CDTs (cytolethal distending toxins) found in several Gram- negative bacteria,
-cell-cycle inhibitor
3.Cif from enteropathogenic and enteroheamorrhagic E.coli, - block mitosis and inhibit clonal expansion of
lymphocytes.
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-Bacterial toxins binding to surface antigens
• Pseudomonas exotoxin A inhibit protein synthesis by catalytically ribosylate EF-2.
• Clostridium perfringens enterotoxic (CPE) investigated for colon, breast, and gastric cancers due to its cytotoxic property.
• Botulinum neurotoxin(BoNT) briefly opens tumors vessels, allowing more effective destruction of cancer by radiotherapy and chemotherapy.
• Some other toxins undergoing on research are - alfa toxin from Stapylococcous aureus, - AC-toxins from Bordetella pertussis - shiga like toxins - cholera toxin
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-BACTERIAL TOXIN CONJUGATED TO LIGAND
• Binding of toxins to cell-binding proteins .e.g Monoclonol antibodies or growth factors, cause regression in growth of cancer by targetting them into the specific sites on cancers.
• For example transferrin-Diphtheria toxin(DT), DT- epidermal growth factor(EGF) in brain tumor and metastatic carcinomas and IL4-PE against human gliboblastoma tumor
• Genetically modified and recombinant toxins e.g chimeric toxins
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BACTERIA AS IMMUNOTHERAPEUTIC AGENTS
• Genetically engineered Attenuated Salmonella typhimurium expressing murine cytokines (IL-2) suppress the growth of tumor.
• Xenogenic DNA vaccine encoding tumor endothelial markers 8(TEM8) carried by attenuated S.typhimurium has been repoetd to generate TEM8-specific CD8 cytotoxic T-cell response after oral administration.
• C.novyi spores after systematic administration destroy adjacent cancer cell and trigger an inflammatory reaction by producing cytokinies such as IL-6, MIP-2, G-CSF, TIMP-1 and KC…
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• CANCER VACCINE- A recombinant Listeria monocytogenes( facultative intracellular bacteria) vaccine strain expressing nucleoprotein (NP)from influenza strainA/PR8/34 has shown great therapeutic potential pre-clinically by regressing growth off microscopic tumors.
• Bacillus calmette-gurein (BCG-CWS) has been used as an effective adjuvent for immunotherapy.
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PROBLEMS WITH BACTERIAL THERAPY
• Toxicity• Infections• Incomplete tumor lysis• DNA mutation
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Conclusion• Live, attenuated bacteria as antitumor agents
and vectors for gene directed enzyme prodrug therapy have emerged as potential strategies.
• VNP20009 and TAPET-CD have been investigated successfully in phase 1 clinical trial.
• Chemeric toxins are also being investigated as future toxin-based anticancer therapies.
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IMPORTANT CLINICAL TRIAL INVOLVING BACTERIAL INTERVENTION IN CANCER
INTERVENTION CLINICAL PRESENT STATUS DISEASE (NUMBER TRAIL PHASE CONDITIONCOMPOUND)
VNP20009 PHASE 1 COMPLETED ADVANCED OR METASTATIC SOLID TUMORS
TAPET-CD HEAD, NECK PHASE 1 COMPLETED ESOPHAGUS CANCER
Tf-CRM 107 PHASE 1 ONGOING BRAIN ENTRAL NERVOUS SYSTEM TUMOR
IL4-PE PHASE 1 ONGOING BRAIN ENTRAL NERVOUS SYSTEM TUMOR
MALIGNANT GILOMA, GLIBLASTOMA MULTIFORME IL3-PE PHASE 1 ONGOING ANAPLASTIC ASTROCYTOMA ANAPLASTIC
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REFERENCES• Jain RK; New approaches for the treatment of cancer. Adv Durg
Delivery rev2001,46:149-168.• Kohwi Y, Imai K, Tamura Z, Hashimoto Y. Antitumor effect of
Bifidobacterium infantis in mice. Gann. 1978; 69:613–618. [PubMed: 729960]
• Kasinskas RW, Forbes NS. Salmonella typhimurium lacking ribose chemoreceptors localize in tumor quiescence and induce apoptosis. Cancer Research. 2007; 67:3201–3209. [PubMed:17409428]
• Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B. Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Natl Acad Sci U S A. 2001; 98:15155–15160.[PubMed: 11724950].