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Posts Tagged ‘Temozolomide’


Notes On Tumor Heterogeneity: Targets and Mechanisms, from the 2015 AACR Meeting in Philadelphia PA

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 1 PM Major Symposium Session on Tumor Heterogeneity: Targets and Mechanism chaired by Dr. Charles Swanton.

Speakers included: Mark J. Smyth, Charles Swanton, René H. Medema, and Catherine J. Wu

Tumor heterogeneity is a common feature of many malignancies, especially the solid tumors and can drive the evolution and adaptation of the growing tumor, complicating therapy and resulting in therapeutic failure, including resistance. This session at AACR described the mechanisms, both genetic and epigenetic, which precipitate intratumor heterogeneity and how mutational processes and chromosomal instability may impact the tumor progression and the origin of driver events during tumor evolution. Finally the session examined possible therapeutic strategies to take advantage of, and overcome, tumor evolution. The session was chaired by Dr. Charles Swanton. For a more complete description of his work, tumor heterogeneity, and an interview on this site please click on the link below:

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

and

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

 

Notes from Charles Swanton, Cancer Research UK; Identifying Drivers of Cancer Diversity

Dr. Swanton’s lecture focused on data from two recent papers from his lab by Franseco Favero and Nicholas McGranahan:

  1. Glioblastoma adaptation Traced Through Decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome (Annals of Oncology, 2015)[1]

This paper described the longitudinal Whole Genome Sequencing (WGS) study of a 35 year old female whose primary glioblastoma (GBM) was followed through temozolomide treatment and ultimately recurrence.

  • In 2008 patient was diagnosed with primary GBM (three biopsies of unrelated sites were Grade II and Grade IV; temozolomide therapy for three years then relapse in 2011
  • WGS of 2 areas of primary tumor showed extensive mutational and copy number heterogeneity; was able to identify clonal TP53 mutations and clonal IDH1 mutation in primary tumor with different patterns of clonality based on grade
  • Amplifications on chromosome 4 and 12 (PDGFRA, KIT, CDK4)
  • After three years of temozolomide multiple translocations found in chromosome 4 and 12 (6 translocations)
  • Clonal IDH1 R132H mutation in primary tumor only at very low frequency in recurrent tumor
  • The WGS on recurrent tumor (sequencing took ONLY 9 days from tumor resection to sequence results) showed mutation cluster in KIT/PDGFRA.PI3K.mTOR axis so patient treated with imatinib
  • However despite rapid sequencing and a personalized approach based on WGS results, tumor progressed and patient died shortly: tumor evolution is HUGE hurdle for personalized medicine

As Dr. Swanton stated:

“we are underestimating the frequency of polyclonal evolution”

  1. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution (Science Translational Medicine, 2015)[2]
  • analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions.
  • identified later subclonal “actionable” mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches.
  • > 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal
  • Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling

Branched chain can converge on single resistance mechanism; clonal resistance (for example to PI3K inhibitors can get multiple PTEN mutations in various metastases

Targeting Tumor Heterogeneity

  • Identify high risk occupants (have to know case history)
  • Mutational landscape interferes with anti-PD1 therapies
  • Low frequency mutations affect outcome

Notes from Dr. Catherine J. Wu, Dana-Farber Cancer Institute: The evolutionary landscape of CLL: Therapeutic implications

  • Clonal evolution a key feature of cancer progression and relapse
  • Hypothesis: evolutionary dynamics (heterogeneity) in chronic lymphocytic leukemia (CLL) contributes to variations in response and disease “tempo”
  • Used whole exome sequencing and copy number data of 149 CLL cases to discover early and late cancer drivers: clonal patterns (Landau et. al, Cell 2013); some drivers correspond to poor clinical outcome
  • Methylation studies suggest that there is epigenetic heterogeneity which may drive CLL clonal evolution
  • Developing methodology to integrate WES to determine mutations with immunogenic potential for development of personalized immunotherapy for CLL and other malignancies

References

  1. Favero F, McGranahan N, Salm M, Birkbak NJ, Sanborn JZ, Benz SC, Becq J, Peden JF, Kingsbury Z, Grocok RJ et al: Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2015, 26(5):880-887.
  2. McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C: Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Science translational medicine 2015, 7(283):283ra254.

 

Other related articles on Tumor Heterogeneity were published in this Open Access Online Scientific Journal, include the following:

 

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

CANCER COMPLEXITY: Heterogeneity in Tumor Progression and Drug Response – 2015 Annual Symposium @Koch Institute for Integrative Cancer Research at MIT – W34, 6/12/2015 9:00 AM EDT – 4:30 PM EDT

My Cancer Genome from Vanderbilt University: Matching Tumor Mutations to Therapies & Clinical Trials

Tumor Imaging and Targeting: Predicting Tumor Response to Treatment: Where we stand?

Mitochondrial Isocitrate Dehydrogenase and Variants

War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert

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In focus: Melanoma therapeutics

 

Author and Curator: Ritu Saxena, Ph.D.

In the last post of Melanoma titled “In focus: Melanoma Genetics”, I discussed the clinical characteristics and the genetics involved in Melanoma.  This post would discuss melanoma therapeutics, both current and novel.

According to the American Cancer Society, more than 76,000 new cases and more than 9100 deaths from melanoma were reported in the United States in 2012[1] Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate.

Melanoma therapeutics

Surgical treatment of cutaneous melanoma employs specific surgical margins depending on the depth of invasion of the tumor and there are specific surgical treatment guidelines of primary, nodal, and metastatic melanoma that surgeons adhere to while treatment. Melanoma researchers have been focusing on developing adjuvant therapies for that would increase the survival post-surgery.

Chemotherapy

Among traditional chemotherapeutic agents, only dacarbazine is FDA approved for the treatment of advanced melanoma (Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36). Dacarbazine is a triazene derivative and alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. Currently, 17 clinical trials are underway to test the efficacy and effectiveness of dacarbazine against melanoma as either a single agent or in combination chemotherapy regimens with other anti-cancer chemotherapeutic agents such as cisplatin, paclitaxel. Temozolomide is a triazene analog of dacarbazine and is approved for the treatment of malignant gliomas. At physiologic pH, it is converted to a short-lived active cytotoxic compound, monomethyl triazeno imidazole carboxamide (MTIC). MTIC methylates DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication. Unlike dacarbazine, which is metabolized to MITC only in the liver, temozolomide is metabolized to MITC at all sites. Temozolomide is administered orally and penetrates well into the central nervous system. Temozolomide is being tested in many combination regimens for patients with melanoma metastatic to the brain (Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24).

Immunotherapy

Melanoma and the immune system are closely related. Hence, immunotherapy has been explored in the treatment of the disease. The two most widely investigated immunotherapy drugs for melanoma are Interferon (IFN)-alpha and Interleukin-2 (IL-2).

The role of IFNalpha-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse was established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. One of these trials, a large randomized multicenter trial performed by the Eastern Cooperative Oncology Group (ECOG), in high-risk melanoma patients showed significant improvements in relapse-free and overall survival with adjuvant IFN-α-2b therapy, compared with standard observation (ECOG 1684). The results of the study led to FDA approval of IFN-α-2b for treatment of melanoma. This study was performed on patients with deep primary tumors without lymph node involvement and node-positive melanomas. In other studies, little antitumor activity has been demonstrated in IFN-α-2b–treated metastatic stage IV melanoma.

Recombinant IL-2 showed an overall response rate of 15-20% in metastatic melanoma and was capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has approved the use of high-dose IL-2 for the therapy of patients with metastatic melanoma. Aldesleukin (Brand name: Proleukin) is a recombinant analog of the endogenous cytokine interleukin-2 (IL-2). It binds to and activates the IL-2 receptor (IL-2R), followed by heterodimerization of the IL-2R beta and gamma(c) cytoplasmic chains; activation of Jak3; and phosphorylation of tyrosine residues on the IL-2R beta chain, resulting in an activated receptor complex (NCI). The activated complex recruits several signaling molecules that act as substrates for regulatory enzymes associated with the complex. It is administered intravenously and stimulates lymphokine-activating killer (LAK) cells, natural killer (NK) cells and the production of cytokines such as gamma interferon (nm|OK). Several clinical trials are currently underway using Aldesleukin to determine the efficacy of combination treatment in melanoma patients.

Another anti-cancer immunotherapeuty-based mechanism involved inhibition of inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab (Brand name: Yervoy) was by FDA for melanoma treatment.  It is a human monoclonal antibody (MAb) T-cell potentiator that specifically blocks CTLA-4. It is approved for inoperable advanced (Stage III) or metastatic (Stage IV) melanoma in newly diagnosed or previously treated patients (nm|OK). The approval, March 25, 2011, was based on a randomized (3:1:1) double-blind double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Patients were randomly assigned to receive either ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n=403); ipilimumab plus vaccine placebo (n=137); or tumor vaccine with placebo (n=136). Patients treated with ipilimumab alone had a median overall survival (OS) of 10 months while those treated with tumor vaccine had a median OS of 6 months. The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus tumor vaccine compared with patients treated with tumor vaccine alone. For more information on the trial, check the clinical trials website, www.clinicaltrials.gov

Signaling pathway inhibitors

Approximately 90% of BRAF gene mutations involve valine (V) to glutamic acid (E) mutation at number 600 residue (V600E). The resulting oncogene product, BRAF (V600E) kinase is highly active and exhibits elevated MAPK pathway. The BRAF(V600E) gene mutation occurs in approximately 60% of melanomas indicating that it could be therapeutically relevant. Vemurafenib (Brand name: Zelboraf) is a novel small-molecule inhibitor of BRAF (V600E) kinase. It selectively binds to the ATP-binding site and inhibits the activity of BRAF (V600E) kinase. Vemurafebib inhibits over active MAPK pathway by inhibiting the mutated BRAF kinase, thereby reducing tumor cell proliferation (NCI). Encouraging results of phase III randomized, open-label, multicenter trial were reported recently at the 2011 ASCO meeting (Chapman PB, et al, ASCO 2011, Abstract LBA4).  The trial compared the novel BRAF inhibitor vemurafenib with dacarbazine in patients with BRAF-mutated melanoma. Previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for BRAF mutation were randomized (1:1) to vemurafenib or dacarbazine. The response rate (RR) was significantly high (48.4%) in vemurafenib treated patients as compared to 5.5% in dacarbazine among the 65% of patients evaluable for RR to date. In addition, vemurafenib was associated with significantly improved OS and PFS compared to dacarbazine in patients with previously untreated BRAF (V600E) mutation bearing patients with metastatic melanoma.

Biochemotherapy

Biochemothreapy combine traditional chemotherapy with immunotherapies, such as IL-2 and IFN-α-2b. These combination therapies seemed promising in phase II trials, however, seven large studies failed to show statistically significant increased overall survival rates for various biochemotherapy regimens in patients with stage IV metastasis (Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8). Owing to inconsistent results of the available studies with regard to benefit including RR, OS and progression time, and consistently high toxicity rates, clinical practice guideline do not recommend biochemotherapy for the treatment of metastatic melanoma (Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89).

Vaccines

The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNalpha (Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46). In fact, recently investigators at the Indiana University Health Goshen Center for Cancer Care (Goshen, IN) conducted a randomized, multicenter phase III trial involving 185 patients with stage IV or locally advanced stage III cutaneous melanoma. The patients were assigned into treatment groups with IL-2 alone or with vaccine (gp100) followed by IL-2. The vaccine-IL-2 group had a significantly improved OR as compared to the IL-2-only group (16% Vs. 6%) and longer progression free survival (2.2 months Vs. 1.6 months). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months Vs. 11.1 months). Thus, a combination of vaccine and immunotherapy showed a better response rate and longer progression-free survival than with interleukin-2 alone in patients with advanced melanoma (Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27).

Which Treatment When?

Earlier, there were essentially two main options for patients suffering from advanced melanoma, dacarbazine and IL-2. Dacarbazine, a chemotherapeutic agent produces modest improvements in survival or symptomatic benefits in most patients. Interleukin-2 -based drugs, on the other hand, induce long-term remissions in a small group of patients but are highly toxic. Recently, FDA approved ipilimumab and vemurafenib for patients with metastatic melanoma. Apart from these, therapies are also aiming at starving the tumor by inhibiting angiogenesis or depleting nutrients essential for cancer growth. Of the antiangiogenic compounds, VEGFR inhibitors SU5416 and AG-013736 demonstrated broad-spectrum antitumor activity in mice bearing xenografts of human cancer cell lines originating from various tissues, including melanoma. In addition, several trials are currently underway to test the efficacy of the drugs in combination. In the future, personalized medicine-based recommendations of novel and existing drugs for melanoma patients might be the way to go.

Reference:

  1. Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36
  2. Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24
  3. Chapman PB, et al, ASCO 2011, Abstract LBA4
  4. Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8
  5. Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89
  6. Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46
  7. Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27
  8. Chudnovsky Y, et al, J Clin Invest, Apr 2005;115(4):813-24.
  9. National Cancer Institute (National Institute of Health)
  10. Clinical Trials reported on the U.S. Institute of Health
  11. New Medicine Oncology KnowledgeBase (nm|OK)

Related articles on Melanoma on this Open Access Online Scientific Journal: 

  1. In focus: Melanoma Genetics Curator- Ritu Saxena, Ph.D.
  2. Thymosin alpha1 and melanoma Author/Editor- Tilda Barliya, Ph.D.
  3. A New Therapy for Melanoma  Reporter- Larry H Bernstein, M.D.
  4. Melanoma: Molecule in Immune System Could Help Treat Dangerous Skin Cancer Reporter: Prabodh Kandala, Ph.D.
  5. Why Braf inhibitors fail to treat melanoma. Reporter: Prabodh Kandala, Ph.D.

 

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