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Treatment Overview > Emerging Therapies & Treatment Targets

Last update: 05/27/2013

DISCONTINUED - 

See  Find Clinical Trials by Type of Agent

 

Index of Emerging Agents and Targets on Lymphomation.org

17-AAG
  Antiangiogenic  
 
ABT-510  AT-101
Anti-bcl-2 (antisense)
Anti-BLyS | Anti-PKC | Anti-VEGF  
  Antibodies (all)  
Apoptosis 
Arsenic Trioxide  
BL22 immunotoxin
BR 2778
 
Bryostatin 
Cell  cycle  arrest  
c-myc

Combination Treatments
CpG oligonucleotides  
 
 CP-461(SAANDS)
Cyclin dependent kinases 
Denileukin Diftitox (ONTAK)
Gallium Nitrate
Histone deacetylase  
Immune therapies 
Immunotoxin with antibody
Microtubules
Mitoguazone

Paclitaxel
PPAR-gamma

Prodigiosin

Proteasome inhibitors (Bortezomib) Velcade
Radio-labeled antibodies  
T-cell therapy
Thalidomide
Topoisomerase-I inhibitors (DX-8951f)
Vaccines
Vaccines Trial Protocols
Xcytrin - (motexafin gadolinium) 
 Zalypsis

TOPIC SEARCH: PubMed/AACR

2ME2 
 AN-238 (somatostatin)    
Anti-cd74
 
 Antisense against Ki-67  Bendamustine 
 Benzodiazepine Bz-423  BMS-247550  
BLyS as target  
CDDO 
Elsamitrucin 
Gemcitabine  
GCS-100  

Gossypol
Fenretinide
  
Indomethacin
 
L5178Y  
MCL-1 
Naproxen  
 NF-Kappa B 
Revlimid (Lenalidomide) - for MDS

SB-715992 - ASCO 
SB203580  
Topotecan 
  SGN-30 
SGN-40
Pixantrone (BR 2778)  
Dipeptidyl peptidase inhibitor (PT-100)  
RAD001 (Everolimus)  
 zebularine - full text background article 

 Also see Immune-based therapies | Investigational agents - LRF.org

Descriptions provided here are intentionally brief. 
Due to time restraints, we are providing links to PubMed abstracts on new agents above.  

Adenovirus
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See Immune Therapies

Adoptive Immunotherapy
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See Immune Therapies

Antiangiogenic

See Antiangiogenic 

Anti-Bcl-2
(antisense)
Oblimersen
Type: genetic / molecular
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Antisense ASCO | ASH | Medscape | ClinicalTrials.gov | PubMed

Bcl-2 is a protein over expressed by a mutated gene in many lymphomas.  This protein seems to prevent cell death (apoptosis) and contribute to drug resistance. Drugs that interfere with the expression of this protein may induce the tumor cells to die and/or make other treatments more effective.

  • AT-101  Web  | ClinicalTrials.gov
  • Liposomal delivery of antisense oligonucleotides for efficient downregulation of Bcl-2 and induction of apoptosis. Cancer Biother Radiopharm. 2002 Jun;17(3):281-9.
    PMID: 12136520  PubMed
  • Antisense drug G3139 for NHL reduces target protein levels  Doctor's Guide
  • cDNA microarray evaluation of non-Hodgkin's lymphoma cells reveals multiple changes in gene expression profiles induced by Bcl-2 antisense (GenasenseTM). ASCO 2002 Abstract 1905
Anti-BLyS
Type: biologic / molecular
PubMed Abstracts
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Anti-BLyS (B lymphocyte stimulator) is a newly identified protein that may provide a target for treatment of b-cell lymphomas. "BLyS is made by immune-cells called monocytes and macrophages. When monocytes and macrophages are activated, BLyS is released and binds to a receptor found only on B cells." - Human Genome Sciences

  • BIOMARKER/TARGET: Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome.   www.bloodjournal.org

    In summary, we believe that BLyS represents an important target in B-cell lymphoma and strategies to inhibit BLyS could therefore translate into important therapeutic modalities.
  • Targeting with LymphoRad  Human Genome Sciences
  • B Lymphocyte Stimulator (BLyS) Background Human Genome Sciences 
  • BLyS and BLyS receptor expression in non-Hodgkin's lymphoma.
    Exp Hematol. 2002 Feb;30(2):135-41. PMID: 11823048  PubMed
  • Radiolabeled BLyS protein (LR131) inhibits neoplastic B cell growth in vivo Year: 2002 Abstract No: 39
Anti-idiotype antibodies
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See Immune Therapies

Anti-PKC-a
Type: biologic / targeted
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PKC-a is a protein important in the continued development and growth of cancer cells. PKC-a is a member of the PKC family, a group of closely related signal transduction proteins, or proteins that regulate the flow of information in and out of cells, and control cell reactions to environmental stimuli. The PKC family plays a role in normal cell function, and is also involved in abnormal cell growth.

  • Protein kinase C inhibitors. Curr Oncol Rep. 2002 Jan;4(1):37-46. Review. PMID: 11734112 - PubMed | Related Abstracts
  • Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica. 2002 Feb;87(2):167-76. PMID: 11836167 PubMed 
anti-VEGF
(Mab)
Type: biologic / antiangiogenic
PubMed Abstracts
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Antibodies
Monoclonal antibodies (Mab)
Type: biologic / immunotherapy

 

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Antibodies are proteins that when infused in the patient seek and bind to "matching" receptors on cancer cells. There are many antibodies being developed for NHL:

Due to the size of this category, we moved it to it's own page.

  • See Antibodies for Lymphoma

  • See Rituxan

  • Anti-CD74 antibody - internalizing properties  prnews 
    "In yet another presentation, Immunomedics' scientists showed that this *rapidly internalizing CD74 antibody*  was very effective in killing human NHL cells in culture and NHL tumors growing in mice when the antibody is conjugated with the anticancer drug, doxorubicin. Dr. Horak commented: "Unexpectedly high 
    efficacy in this preclinical model was found with a single injection of this antibody-drug conjugate, even in advanced disease." 

    Cure of SCID Mice Bearing Human B-Lymphoma Xenografts by an Anti-CD74 Antibody-Anthracycline Drug Conjugate. Clin Cancer Res. 2003 Dec 15;9(17):6567-71. PMID: 14695162 | Related articles
Apoptosis

Programmed cell death as signaled by the nuclei in normally functioning cells when age or state of cell health and condition dictates.

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  • Pan-Bcl2 Family Inhibitor GX15-070  newswire.ca 

    GX15-070 is a small molecule specifically designed to inhibit all relevant members of the Bcl-2 protein family, a validated cancer target, thus restoring the natural cell death process of apoptosis.

 

Arsenic trioxide
Type: apoptotic & differentiation
PubMed Abstracts
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Arsenic trioxide may induce cell death (apoptosis) and normalization (differentiation) thru novel pathway(s). Approved for leukemia.

Bryostatin
Type: cytotoxic and immunomodulatory
PubMed Abstracts
Clinical Trials
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Bryostatin - Possible mechanism of action: "Bryostatin-1 is believed to bind to the regulatory domain of the PKC enzyme suggesting a mechanism of action distinct from other kinase modulators in development."  gpc-ag.com
 
  • ASH: Bryostatin Less Than Impressive in Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin's Lymphoma  DoctorsGuide
BR 2778 (Pixantrone)
Clinical Trials
Type: novel aza-anthracenedione
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"BBR 2778 is a novel analogue of anthracenediones which acts by DNA intercalation and inhibition of DNA topo-isomerase II."  ASCO
 
  • Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin's lymphoma. Ann Oncol. 2001 May;12(5):661-7  abstract
c-myc
Type: biologic / molecular target
PubMed Abstracts
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c-myc is a gene that's over expressed in a variety of malignancies including lymphomas, and leukemias. It's thought that the oncogenic (cancer promoting) "properties of C-Myc arise from gene amplification or chromosome translocation." Anti-c-myc oligonucleotides are being investigated as potential treatments that target this gene.

Cell cycle arrest
Type: biologic / molecular
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"The mechanisms underlying this effect are mediated by the adenosine A3 receptor and involve cell cycle arrest and the inhibition of the telomeric signal, the scientists have determined."

Combination treatments
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Numerous combinations and sequences of therapies are possible. Of interest to many is the possibility of combining low toxic therapies to better manage indolent NHL without suppressing bone marrow function or burning treatment bridges.

CpG oligonucleotides
Type: DNA / immunotherapy
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"CpG activates the immune system in the way it evolved to be activated, by detection of bacterial products. You activate a well-orchestrated symphony of responses that synergize with each other." Everything enters on cue: cells, cytokines, and actions. Toxicity is minimal. Immune factors, although great medicines, drive "an artificial, disorganized response. You have to use very high doses to get any activity, and because of that, you also get a lot of toxicity."
 
  • Background: Coley Toxin's Hidden Message From a 19th century mystery comes a potential new class of drugs: CpG oligonucleotides
  • Boosting Mabs and vaccines? CpG-DNA activates dendritic cells in vivo: T helper cell-independent cytotoxic T cell responses to soluble proteins. Eur J Immunol. 2000 Dec;30(12):3591-7. Related abstracts

 

CP461 / OS1-461
(SAANDs)
Type: biologic / apoptotic
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Selective apoptotic anti-neoplastic drugs (SAANDs). Induce apoptosis in a broad range of cancerous and precancerous cells via inhibition of cyclic GMP phosphodiesterase (cG PDE) and activation of PKG.  (* Safe profile, oral administration.)

Cyclin dependent kinases
(CDKs)
Type: biologic / molecular
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Cyclin dependent kinases (CDKs) are regulators of cell cycle progression.

  • Review - NIH
  • Flavopiridol - PubMed Phase 2 trials with infusional flavopiridol in several tumor types, other schedules and combination with standard chemotherapies are being assessed.
Denileukin diftitox (ONTAK) 
type: targeted
ClinicalTrials.gov
PubMed Abstracts

 

 

Denileukin diftitox (den-i-LOO-kin DIF-ti-tocks) is a fusion protein designed to direct the cytocidal action of diphtheria toxin to cells which express the IL-2 receptor. The human IL-2 receptor exists in three forms, low (CD25), intermediate (CD122/CD132) and high (CD25/CD122/CD132) affinity. The high affinity form of this receptor is usually found only on activated T lymphocytes, activated B lymphocytes and activated macrophages. 

Malignant cells expressing one or more of the subunits of the IL-2 receptor are found in certain leukemias and lymphomas including cutaneous T-cell lymphoma (CTCL)1. Ex vivo studies suggest that denileukin diftitox interacts with the high affinity IL-2 receptor on the cell surface and inhibits cellular protein synthesis, resulting in cell death within hours." [1]

  1. Product info from Ligand: ligand.com/pdf/Ontak - PDF | cancersourcemd.com 
  2. About side effects  Medscape 
  3. Interim analysis of a phase II study of denileukin diftitox (ONTAK) for B and T-cell non-Hodgkin's lymphoma  Abstract No: 2292 
  4. Remission of follicular non-Hodgkin's lymphoma with denileukin diftitox (ONTAK) after progression during rituximab, CHOP and fludarabine therapy. Leuk Lymphoma. 2003 Apr;44(4):731-3. PMID: 12769354
  5. Denileukin diftitox for GvHD tops news at Tandem BMT  hemonctoday.com Mar 2004
Gallium Nitrate
Type:  targeted
ClinicalTrials.gov
PubMed Abstracts
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Gallium Nitrate (Ganite®) was previously received FDA approval as treatment for cancer-related hypercalcemia. "Gallium nitrate causes little myelosuppression and is therefore well tolerated by patients with advanced disease who have received extensive prior therapy. Given its unique mechanism of action, the high level of single-agent activity in published clinical trials, the absence of significant myelosuppression, and the potential lack of cross-resistance, further clinical study of gallium nitrate both alone and in combination with other active agents is warranted." 3

  1. About - GentaGenta-Trials
  2. Gallium Nitrate in the treatment of lymphoma  Related PubMed Articles
  3. Gallium nitrate in the treatment of lymphoma. Semin Oncol. 2003 Apr;30(2 Suppl 5):25-33. Review. PMID: 12776257
  4. About the gallium nitrate (for treatment of hypercalcemia)  MedlinePlus
  5. Identification of biomarkers for tumor sensitivity and resistance to Ganite aacr03.agora.com
     
Histone deacetylase (HDAC) inhibitor
Type: biologic / molecular
ClinicalTrials.gov
PubMed Abstracts | Mechanisms
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"Deacetylation of histones results in condensed chromatin structure and repression of gene transcription." [1]

PXD101 (example) is a small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents, and is currently being evaluated in a Phase II clinical trial for the treatment of multiple myeloma.   HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes,
and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents. In August 2004, 5

  1. Clinical experience with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in heavily pre-treated patients with hematological malignancies - ASCO 2003
  2. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report - full text  Blood 2001
  3. The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses  pubmedcentral.nih.gov
  4. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report.
    Blood. 2001 Nov 1;98(9):2865-8. PMID: 11675364
  5. New Preclinical Data on HDAC Inhibitor PXD101 Demonstrates Down Regulation of Common Mechanism of Cancer Therapy Resistance  topotarget.com pressrelease_20042005.pdf 

     

Immune therapies
Type:  immunotherapy 
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Technologies that seek to enhance or direct the immune system to fight cancer. 

We have moved this growing section to a separate page:

  • Immune-based therapies for lymphomas - PAL
Immunotoxin bound 
to antibody
Type: targeted immunotherapy / cytotoxic
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A new fusion toxin, BL22, targets the CD22 antigen and shows marked activity in the treatment of hairy cell leukemia. Other cd-22 b-cell lymphomas may well respond.

Measles virus
Type: immunotherapy
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Safe, live attenuated measles virus (MV) vaccines regress NHL tumors in mice.

Microtubules
Type: molecular
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Microtubules are structures involved in cell division. Anti-microtubule drugs disturb the assembly of the microtubules and thus prevent the cell from dividing. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. Anti-microtubule drugs stop the microtubules from breaking down; cancer cells become so clogged with microtubules that they cannot grow and divide. (NCI)

Mitoguazone
Type: apoptotic
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"Mitoguazone (methylglyoxal bisguanylhydrazone, methyl-GAG or MGBG) is a synthetic polycarbonyl derivative with activity in patients with Hodgkin's and non-Hodgkin's lymphoma, head and neck cancer, prostate cancer, and esophageal cancer. Mitoguazone has also recently been documented to have activity in patients with AIDS-related lymphoma. Among anticancer drugs, mitoguazone has a unique mechanism of action via interference with the polyamine biosynthetic pathway." [1]

  1. Mitoguazone induces apoptosis via a p53-independent mechanism.
    Anticancer Drugs. 1998 Aug;9(7):635-40. PMID: 9773808  PubMed | Related abstracts
Paclitaxel
Type: apoptotic
Studies in ClinicalTrials.gov
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  • A phase I and pharmacokinetic (PK) study of PEG-paclitaxel in patients with advanced solid tumors  ASCO
  • Resveratrol (pigment in red grapes) modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to Paclitaxel-induced apoptosis. Mol Cancer Ther. 2004 Jan;3(1):71-84. PMID: 14749477 | Related articles
PPAR-gamma
Type: apoptotic
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"PPAR-gamma agonists may serve as a counterbalance to the stimulating effects of PGE2, which promotes B-cell differentiation. The use of prostaglandins, such as 15d-PGJ2, and synthetic PPAR-gamma agonists to induce apoptosis in B lineage cells may lead to the development of therapies for fatal PGE2-resistant B lymphomas.
" [1]

  1. PPAR-gamma-mediated regulation of normal and malignant B lineage cells.
    Ann N Y Acad Sci. 2000 Apr;905:97-109.
    PMID: 10818446 PubMed | Related Abstracts
Prodigiosin
Type: apoptotic
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Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukemia. Leukemia. 2003 Apr;17(4):746-50. PMID: 12682632 - PubMed

Velcade 
 
(Proteasome
inhibitor) PS-341 / Bortezomib 
Type: biologic / molecular / apoptotic
PubMed Abstracts
Studies in ClinicalTrials.gov
More Studies in ClinicalTrials.gov
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Thought to interfere with the function of an important cellular protein complex, and provokes cells to program their own destruction. "The results from this study (phase I) are exciting because PS-341 was able to benefit several patients who were not helped by standard chemotherapy," Orlowski said. PS-341 seemed particularly active in two diseases: multiple myeloma and non-Hodgkin's lymphoma. Also called LDP-341

  • Drug-induced cutaneous vasculitis (inflammation of the blood vessels) in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib (Velcade): a possible surrogate marker of response? Br J Haematol. 2006 Aug;134(4):391-8. PMID: 16882131
  • Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma. J Clin Oncol. 2004 Dec 21;  PMID: 15613697
  • Phase II Clinical Experience With the Novel Proteasome Inhibitor Bortezomib [Velcade] in Patients With Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma. J Clin Oncol. 2004 Dec 21; PMID: 15613699
  • Marked clinical activity of the novel proteasome inhibitor bortezomib in patients with relapsed follicular (RL) and mantle cell lymphoma (MCL). ASCO 2004 Abstract No: 6582 
  • Promising Activity of the Proteasome Inhibitor Bortezomib (Velcade) in the Treatment of Indolent Non-Hodgkins Lymphoma and Mantle Cell Lymphoma  ASH 2003
  • Velcade - Full prescribing info  PDF 
  • Millennium says anti-cancer proteasome inhibitor safe over longer term  ASCO
  • FDA Approves Velcade (PS-341) for Multiple Myeloma Treatment  FDA.gov  
  • Proteasome: A New Target for Novel Drug Therapies  Medscape (free login req.)
  • Proteasome inhibitors in the treatment of B-cell malignancies.
    Clin Lymphoma. 2002 Jun;3(1):49-55. PMID: 12141956  PubMed
  • Full prescribing information - millennium  PDF
  • About PS-341  Science Daily  
Radio-labeled antibodies
Type: targeted immunotherapy / radiation
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Antibodies deliver targeted radiation to cancer cells, and reduces exposure to normal cells. Bone marrow toxicity is common.

Telomerase
as an antigen
Type: biologic / molecular
PubMed Abstracts
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Approved for other uses. Early testing for NHL) Earlier study "demonstrated that the RNA encoding the catalytic reverse transcriptase protein component of human telomerase (hTERT RNA), when introduced into dendritic cells, can stimulate the immune system to produce cytotoxic T lymphocytes (CTLs, or killer-T cells) capable of recognizing and destroying telomerase-positive cancer cells." (Lymphomas are among cancers in this category.) 

  • Treatment target: Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders. Blood. 2004 Jun 15;103(12):4644-9. Epub 2004 Feb 26. PMID: 14988160 
  • Telomerase inhibition with an oligonucleotide telomerase template antagonist: in vitro and in vivo studies in multiple myeloma and lymphoma. Blood. 2003 Sep 11 [Epub ahead of print] PMID: 12969977  | Related
  • Telomeres and telomerase in hematologic neoplasia. Oncogene. 2002 Jan 21;21(4):680-7. Review. PMID: 11850796  PubMed
  • Telomerase as antigen for cancer immunotherapy 
Thalidomide
Type: biologic / immunotherapy / antiangiogenic
Studies in ClinicalTrials.gov
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Approved for other uses. So far best activity seen for myeloma.

Topoisomerase-I inhibitors
Type: biologic
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Inhibits enzyme that changes the degree of supercoiling in DNA by cutting one or both strands.

  • Irinotecan in Relapsed or Refractory Non-Hodgkin’s Lymphomas, Vol 16, No 8, Suppl 7 (August 2002)  cancernetwork.com
  • DX-8951f:  A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res. 1995 Aug;86(8):776-82. abstract | MSKCC study
  • Role in treatment of NHL 
Motexafin gadolinium (MGd)

Topic Search: PubMed

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"Motexafin gadolinium (MGd) belongs to a class of compounds known as texaphyrins, which are expanded porphyrin macromolecules capable of forming complexes with large cations such as lanthanides. 

In tumor cells, MGd generates reactive oxygen species (ROS) by accepting electrons from cellular reducing metabolites and transferring them to oxygen. This results in disruption of cellular metabolism and predisposes the tumor cell to apoptosis when an additional stressor, such as radiation or chemotherapy, is applied (11, 12). 

Moreover, elegant tumor-specificity and intracellular localization of MGd has been demonstrated by DeStasio et al. and Woodburn et al. (11, 13). The precise mechanisms for this tumor specificity are not well identified. In other clinical trials, such as the one reported by Carde et al. (14), MGd has been shown not only to be tumor specific, but also long-lived with tumor retention periods of weeks to months. Data from UCLA by Ford et al., suggest that this retention and consequential “enhancement” on T1 MRI is a function of the dose of MGd (15)."

source: www.tcrt.org

 

Zalypsis® 
 (Renieramycins)

Topic Search: PubMed

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Zalypsis® is a novel chemical entity related to the marine natural compounds Jorumycin and the family of Renieramycins, obtained from molluscs and sponges, respectively. Zalypsis binds to DNA and is cytotoxic; however, it does not activate the “DNA damage checkpoint” response. Thus, Zalypsis has cytotoxic effects dependent on DNA binding that are not associated with DNA damage. - pharmamar.com 

Clinical trial for lymphoma: clinicaltrials.gov NCT00359294 

 
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professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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